Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a heterogeneous group of debilitating disorders with multifactorial etiologies and pathogeneses that manifest distinct molecular mechanisms and clinical manifestations with abnormal protein dynamics and impaired bioenergetics. Mitochondrial dysfunction is emerging as an important feature in the etiopathogenesis of these age-related neurodegenerative diseases. The prevalence and incidence of these diseases is on the rise with the increasing global population and average lifespan. Although many therapeutic approaches have been tested, there are currently no effective treatment routes for the prevention or cure of these diseases. We present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in these diseases and highlight recent advances in novel therapeutic strategies targeting neuronal bioenergetics as potential approach for treating these diseases.

Center for Translational Medicine International Clinical Research Centre St Anne's University Hospital Brno Czech Republic

Neurodegeneration Therapeutics 3050A Berkmar Drive Charlottesville VA USA

See more in PubMed

Abramov AY, Berezhnov AV, Fedotova EI, Zinchenko VP, Dolgacheva LP. Interaction of misfolded proteins and mitochondria in neurodegenerative disorders. Biochem Soc Trans. 2017;45:1025–1033. PubMed

Akimoto T, Pohnert SC, Li P, Zhang M, Gumbs C, Rosenberg PB, Williams RS, Yan Z. Exercise stimulates Pgc-1alpha transcription in skeletal muscle through activation of the p38 MAPK pathway. J Biol Chem. 2005;280:19587–19593. PubMed

Alto NM, Soderling J, Scott JD. Rab32 is an A-kinase anchoring protein and participates in mitochondrial dynamics. J Cell Sci. 2002;158:659–668. PubMed PMC

Antonini A, Leenders KL, Spiegel R, Meier D, Vontobel P, Weigell-Weber M, Sanchez-Pernaute R, de Yébenez JG, Boesiger P, Weindl A, Maguire RP. Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington’s disease. Brain. 1996;119(Pt 6):2085–2095. PubMed

Armstrong JS. Mitochondrial medicine: Pharmacological targeting of mitochondria in disease. Br J Pharmacol. 2007;151:1154–1165. PubMed PMC

Ashrafi G, Schlehe JS, LaVoie MJ, Schwarz TL. Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol. 2014;206:655–670. PubMed PMC

Attwell D, Laughlin SB. An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab. 2001;21:1133–1145. PubMed

Babenko VA, Silachev DN, Zorova LD, Pevzner IB, Khutornenko AA, Plotnikov EY, Sukhikh GT, Zorov DB. Improving the post-stroke therapeutic potency of mesenchymal multipotent stromal cells by Cocultivation with cortical neurons: the role of crosstalk between cells. Stem Cells Transl Med. 2015;4:1011–1020. PubMed PMC

Bacman SR, Williams SL, Pinto M, Peralta S, Moraes CT. Specific elimination of mutant mitochondrial genomes in patient-derived cells by mitoTALENs. Nat Med. 2013;19:1111–1113. PubMed PMC

Bacman SR, Kauppila JHK, Pereira CV, Nissanka N, Miranda M, Pinto M, Williams SL, Larsson NG, Stewart JB, Moraes CT. MitoTALEN reduces mutant mtDNA load and restores tRNAAla levels in a mouse model of heteroplasmic mtDNA mutation. Nat Med. 2018;24:1696–1700. PubMed PMC

Banerjee K, Sinha M, Pham Cle L, Jana S, Chanda D, Cappai R, Chakrabarti S. Alpha-synuclein induced membrane depolarization and loss of phosphorylation capacity of isolated rat brain mitochondria: implications in Parkinson’s disease. FEBS Lett. 2010;584:1571–1576. PubMed

Baraniak PR, McDevitt TC. Stem cell paracrine actions and tissue regeneration. Regen Med. 2010;5:121–143. PubMed PMC

Bell SM, Barnes K, Clemmens H, Al-Rafiah AR, Al-Ofi EA, Leech V, Bandmann O, Shaw PJ, Blackburn DJ, Ferraiuolo L, Mortiboys H. Ursodeoxycholic acid improves mitochondrial function and redistributes Drp1 in fibroblasts from patients with either sporadic or familial Alzheimer’s disease. J Mol Biol. 2018;430:3942–3953. PubMed PMC

Benatar M. Lost in translation: treatment trials in the SOD1 mouse and in human ALS. Neurobiol Dis. 2007;26:1–13. PubMed

Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet. 2006;38:515–517. PubMed

Bera AK, Ghosh S, Das S. Mitochondrial VDAC can be phosphorylated by cyclic AMP-dependent protein kinase. Biochem Biophys Res Commun. 1995;209:213–217. PubMed

Bergendi L BL, Ďuracková Z, Ferenčik M. Chemistry, physiology and pathology of free radicals. Life Sci. 1999;65:1865–1874. PubMed

Bezprozvanny I, Hayden MR. Deranged neuronal calcium signaling and Huntington disease. Biochem Biophys Res Commun. 2004;322:1310–1317. PubMed

Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR. Oxidative stress and Parkinson’s disease. Front Neuroanat. 2015;9:91. PubMed PMC

Blesa JR, Hernández-Yago J. Distinct functional contributions of 2 GABP-NRF-2 recognition sites within the context of the human TOMM70 promoter. Biochem Cell Biol. 2006;84:813–822. PubMed

Borghammer P, Chakravarty M, Jonsdottir KY, Sato N, Matsuda H, Ito K, Arahata Y, Kato T, Gjedde A. Cortical hypometabolism and hypoperfusion in Parkinson’s disease is extensive: probably even at early disease stages. Brain Struct Funct. 2010;214:303–317. PubMed

Calì T, Ottolini D, Brini M. Mitochondrial Ca2+ and neurodegeneration. Cell Calcium. 2012;52:73–85. PubMed PMC

Camandola S, Mattson MP. Brain metabolism in health, aging, and neurodegeneration. EMBO J. 2017;36:1474–1492. PubMed PMC

Cardoso SM, Proenca MT, Santos S, Santana I, Oliveira CR. Cytochrome c oxidase is decreased in Alzheimer’s disease platelets. Neurobiol Aging. 2004;25:105–110. PubMed

Carelli V, Chan DC. Mitochondrial DNA: impacting central and peripheral nervous systems. Neuron. 2014;84:1126–1142. PubMed PMC

Carlucci A, Adornetto A, Scorziello A, Viggiano D, Foca M, Cuomo O. Proteolysis of AKAP121 regulates mitochondrial activity during cellular hypoxia and brain ischaemia. EMBO J. 2008;27:1073–8410. PubMed PMC

Caspersen C, Wang N, Yao J, Sosunov A, Chen X, Lustbader JW, Xu HW, Stern D, McKhann G, Yan SD. Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease. FASEB J. 2005;19:2040–2041. PubMed

Cassano P, Sciancalepore AG, Lezza AM, Leeuwenburgh C, Cantatore P, Gadaleta MN. Tissue-specific effect of age and caloric restriction diet on mitochondrial DNA content. Rejuvenation Res. 2006;9:211–214. PubMed

Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T, Kurth MJ, Shaw JT, Hinshaw JE, Green DR, Nunnari J. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell. 2008;14:193–204. PubMed PMC

Castellani R, Hirai K, Aliev G, Drew KL, Nunomura A, Takeda A, Cash AD, Obrenovich ME, Perry G, Smith MA. Role of mitochondrial dysfunction in Alzheimer’s disease. J Neurosci Res. 2002;70:357–360. PubMed

Cerqueira FM, Cunha FM, Laurindo FR, Kowaltowski AJ. Calorie restriction increases cerebral mitochondrial respiratory capacity in a NO•-mediated mechanism: impact on neuronal survival. Free Radic Biol Med. 2012;52:123641. PubMed

Cha MY, Kim DK, Mook-Jung I. The role of mitochondrial DNA mutation on neurodegenerative diseases. Exp Mol Med 47. 2015:e150. PubMed PMC

Chandel NS. Evolution of mitochondria as signaling organelles. Cell Metab. 2015;22:204–206. PubMed

Chang JC, Wu SL, Liu KH, Chen YH, Chuang CS, Cheng FC, Su HL, Wei YH, Kuo SJ, Liu CS. Allogeneic/xenogeneic transplantation of peptide-labeled mitochondria in Parkinson’s disease: restoration of mitochondria functions and attenuation of 6-hydroxydopamine-induced neurotoxicity. Transl Res. 2016;170:40–56. PubMed

Chaturvedi RK, Adhihetty P, Shukla S, Hennessy T, Calingasan N, Yang L, Starkov A, Kiaei M, Cannella M, Sassone J, Ciammola A, Squitieri F, Beal MF. Impaired PGC-1alpha function in muscle in Huntington’s disease. Hum Mol Genet. 2009;18:3048–3065. PubMed PMC

Chen H, Chan DC. Mitochondrial dynamics-fusion, fission, movement, andmitophagy-in neurodegenerative diseases. Hum Mol Genet. 2009;18:R169–176. PubMed PMC

Chen H, Chomyn A, Chan D. Disruption of fusion results in mitochondrial heterogeneity and dysfunction J Biol Chem 280:26185-26192. 2005 PubMed

Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol. 2003;160:189–200. PubMed PMC

Chen Q, Prior M, Dargusch R, Roberts A, Riek R, Eichmann C, Chiruta C, Akaishi T, Abe K, Maher P, Schubert D. A novel neurotrophic drug for cognitive enhancement and Alzheimer’s disease. PLoS One 6. 2011:e27865. PubMed PMC

Chen W, Zhang X, Huang W. Role of physical exercise in Alzheimer’s disease (Review) Biomedical Reports. 2016;4:403–407. PubMed PMC

Cheng X, Siow RC, Mann GE. Impaired redox signaling and antioxidant gene expression in endothelial cells in diabetes: a role for mitochondria and the nuclear factor-E2-related factor 2-Kelch-like ECH-associated protein 1 defense pathway. Antioxid Redox Signal. 2011;14:469–487. PubMed

Chiang MC, Chern Y, Juo CG. The dysfunction of hepatic transcriptional factors in mice with Huntington’s disease. Biochim Biophys Acta. 2011;1812:1111–1120. PubMed

Chien L, Liang MZ, Chang CY, Wang C, Chen L. Mitochondrial therapy promotes regeneration of injured hippocampal neurons. Biochim Biophys Acta. 2018;1864:3001–3012. PubMed

Cho DH, Nakamura T, Lipton SA. Mitochondrial dynamics in cell death and neurodegeneration. Cell Mol Life Sci. 2010;67:3435–3447. PubMed PMC

Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science. 2009;324:102–105. PubMed PMC

Chondrogianni N, Voutetakis K, Kapetanou M, Delitsikou V, Papaevgeniou N, Sakellari M, Lefaki M, Filippopoulou K, Gonos ES. Proteasome activation: An innovative promising approach for delaying aging and retarding age-related diseases. Ageing Res Rev. 2015;23:37–55. PubMed

Choo YS, Johnson GVW, MacDonald M, Detloff PJ, Lesort M. Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release. Hum Mol Genet. 2004;13:1407–1420. PubMed

Ciarmiello A, Cannella M, Lastoria S, Simonelli M, Frati L, Rubinsztein DC, Squitieri F. Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington’s disease. J Nucl Med. 2006;47:215–222. PubMed

Cipolat S, Martins de Brito O, Dal Zilio B, Scorrano L. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci U S A. 2004;101:15927–15932. PubMed PMC

Civitarese AE, MacLean PS, Carling S, Kerr-Bayles L, McMillan RP, Pierce A, Becker TC, Moro C, Finlayson J, Lefort N, Newgard CB, Mandarino L, Cefalu W, Walder K, Collier GR, Hulver MW, Smith SR, Ravussin E. Regulation of skeletal muscle oxidative capacity and insulin signaling by the mitochondrial rhomboid protease PARL. Cell Metab. 2010;11:412–426. PubMed PMC

Cogliati S, Enriquez JA, Scorrano L. Mitochondrial cristae: where beauty meets functionality. Trends Biochem Sci. 2016;41:261–273. PubMed

Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM. Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat Commun. 2014;5:3557. PubMed PMC

Cozzolino M, Carri MT. Mitochondrial dysfunction in ALS. Prog Neurobiol. 2012;97:54–66. PubMed

Craven L, Alston CL, Taylor RW, Turnbull DM. Recent advances in mitochondrial Disease. Annu Rev Genomics Hum Genet. 2017;18:257–275. PubMed

Crow JP, Ye YZ, Strong M, Kirk M, Barnes S, Beckman JS. Superoxide dismutase catalyzes nitration of tyrosines by peroxynitrite in the rod and head domains of neurofilament-L. J Neurochem. 1997;69:1945–1953. PubMed

Dal Vechio FH, Cerqueira F, Augusto O, Lopes R, Demasi M. Peptides that activate the 20S proteasome by gate opening increased oxidized protein removal and reduced protein aggregation. Free Radic Biol Med. 2014;67:304–313. PubMed

Dantuma NP, Bott LC. The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution. Front Mol Neurosci. 2014;7:70. PubMed PMC

Das S, Wong R, Rajapakse N, Murphy E, Steenbergen C. Glycogen synthase kinase 3 inhibition slows mitochondrial adenine nucleotide transport and regulates voltage-dependent anion channel phosphorylation. Circ Res. 2008;103:983–991. PubMed PMC

Daugherty D, Goldberg J, Fischer W, Dargusch R, Maher P, Schubert D. A novel Alzheimer’s disease drug candidate targeting inflammation and fatty acid metabolism. Alzheimers Res Ther. 2017;9:50. PubMed PMC

de Castro IP, Martins LM, Tufi R. Mitochondrial quality control and neurological disease: an emerging connection. Expert Rev Mol Med 12. 2010:e12. PubMed PMC

De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature. 2011;476:336–340. PubMed PMC

Deckel AW. Nitric oxide and nitric oxide synthase in Huntington’s disease. J Neurosci Res. 2001;64:99–107. PubMed

Deckel AW, Tang V, Nuttal D, Gary K, Elder R. Altered neuronal nitric oxide synthase expression contributes to disease progression in Huntington’s disease transgenic mice. Brain Res. 2002;939:76–86. PubMed

Dempsey C, Rubio Araiz A, Bryson KJ, Finucane O, Larkin C, Mills EL, Robertson AAB, Cooper MA, O’Neill LAJ, Lynch MA. Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice. Brain Behav Immun. 2017;61:306–316. PubMed

Dhandapani PK, Lyyski AM, Paulin L, Khan NA, Suomalainen A, Auvinen P, Dufour E, Szibor M, Jacobs HT. Phenotypic effects of dietary stress in combination with a respiratory chain bypass in mice. Physiol Rep 7. 2019:e14159. PubMed PMC

Dheen ST, Kaur C, Ling EA. Microglial activation and its implications in the brain diseases. Curr Med Chem. 2007;14:1189–1197. PubMed

Di Maio R, Barrett PJ, Hoffman EK, Barrett CW, Zharikov A, Borah A, Hu X, McCoy J, Chu CT, Burton EA, Hastings TG, Greenamyre JT. α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease. Sci Transl Med. 2016;8:342ra78. PubMed PMC

Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3 beta regulates cyclin D1 proteolysis and subcellular localisation. Genes Dev. 1998;12:3499–3511. PubMed PMC

Ding WX, Yin XM. Mitophagy, mechanisms, pathophysiological roles, and analysis. Biol Chem. 2012;393:547–564. PubMed PMC

Dionísio PA, Amaral JD, Ribeiro MF, Lo AC, D’Hooge R, Rodrigues CMP. Amyloid-β pathology is attenuated by tauroursodeoxycholic acid treatment in APP/PS1 mice after disease onset. Neurobiol Aging. 2015;36:228–240. PubMed

Dong Z, Saikumar P, Weinberg JM, Venkatachalan MA. Calcium in cell injury and death. Annu Rev Pathol Mech Dis. 2006;1:405–434. PubMed

Drose S, Brandt U. Molecular mechanisms of superoxide production by the mitochondrial respiratory chain. Adv Exp Med Biol. 2012;748:145–169. PubMed

Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O, Chen JX, Yan SD. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med. 2008;14:1097–1105. PubMed PMC

Duan M, Tu J, Lu Z. Recent advances in detecting mitochondrial DNA heteroplasmic variations. Molecules. 2018;23:2. PubMed PMC

Duan W, Li X, Shi J, Guo Y, Li Z, Li C. Mutant TAR DNA-binding protein-43 induces oxidative injury in motor neuron-like cell. Neuroscience. 2010;169:1621–1629. PubMed

East DA, Fagiani F, Crosby J, Georgakopoulos ND, Bertrand H, Schaap M, Campanella M. PMI: A ΔΨm independent pharmacological regulator of mitophagy. Chem Biol. 2014;21:1585–1596. PubMed PMC

Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. 2011;331:456–461. PubMed PMC

Eilam R, Peter Y, Groner Y, Segal M. Late degeneration of nigro-striatal neurons in ATM−/− mice. Neuroscience. 2003;121:83–98. PubMed

Eisner V, Picard M, Hajnóczky G. Mitochondrial dynamics in adaptive and maladaptive cellular stress responses. Nat Cell Biol. 2018;20:755–765. PubMed PMC

El-Khoury R, Dufour E, Rak M, Ramanantsoa N, Grandchamp N, Csaba Z, Duvillié B, Bénit P, Gallego J, Gressens P, Sarkis C, Jacobs HT, Rustin P. Alternative oxidase expression in the mouse enables bypassing cytochrome c oxidase blockade and limits mitochondrial ROS overproduction. PLoS Genet 9. 2013:e1003182. PubMed PMC

Enokido Y, Tamura T, Ito H, Arumughan A, Komuro A, Shiwaku H, Sone M, Foulle R, Sawada H, Ishiguro H, Ono T, Murata M, Kanazawa I, Tomilin N, Tagawa K, Wanker EE, Okazawa H. Mutant huntingtin impairs Ku70-mediated DNA repair. J Cell Biol. 2010;189:425–443. PubMed PMC

Erkkinen MG, Kim MO, Geschwind MD. Clinical neurology and epidemiology of the major neurodegenerative diseases. Cold Spring Harb Perspect Biol 10. 2018:a033118. PubMed PMC

Eschbach J, Schwalenstöcker B, Soyal SM, Bayer H, Wiesner D, Akimoto C, Nilsson AC, Birve A, Meyer T, Dupuis L, Danzer KM, Andersen PM, Witting A, Ludolph AC, Patsch W, Weydt P. PGC-1α is a male-specific disease modifier of human and experimental amyotrophic lateral sclerosis. Hum Mol Genet. 2013;22:3477–3484. PubMed

Espino J, Bejarano I, Redondo PC, Rosado JA, Barriga C, Reiter RJ, Pariente JA, Rodríguez AB. Melatonin reduces apoptosis induced by calcium signaling in human leukocytes: Evidence for the involvement of mitochondria and Bax activation. J Membr Biol. 2010;233(1-3):105–118. PubMed

Evans MJ, Scarpulla RC. NRF-1: a trans-activator of nuclear-encoded respiratory genes in animal cells. Genes Dev. 1990;4:1023-1034. PubMed

Fang Y, Hu XH, Jia ZG, Xu MH, Guo ZY, Gao FH. Tiron protects against UVB-induced senescence-like characteristics in human dermal fibroblasts by the inhibition of superoxide anion production and glutathione depletion. Australas J Dermatol. 2012;53:172–180. PubMed

Ferlazzo ML, Sonzogni L, Granzotto A, Bodgi L, Lartin O, Devic C, Vogin G, Pereira S, Foray N. Mutations of the Huntington’s disease protein impact on the ATM-dependent signaling and repair pathways of the radiation-induced DNA double-strand breaks: corrective effect of statins and bisphosphonates. Mol Neurobiol. 2014;49:1200–1211. PubMed

Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr. 2011;93:884S-890S. PubMed PMC

Ferreira IL, Nascimento MV, Ribeiro M, Almeida S, Cardoso SM, Grazina M, Pratas J, Santos MJ, Januário C, Oliveira CR, Rego AC. Mitochondrial-dependent apoptosis in Huntington’s disease human cybrids. Exp Neurol. 2010;222:243–255. PubMed

Ferreiro E, Oliveira CR, Pereira CMF. The release of calcium from the endoplasmic reticulum induced by amyloid-beta and prion peptides activates the mitochondrial apoptotic pathway. Neurobiol Dis. 2008;30:331–342. PubMed

Flint Beal M. Mitochondria and the pathogenesis of ALS. Brain. 2000;123:1291–1292. PubMed

Franco-Iborra S, Vila M, Perier C. The Parkinson disease mitochondrial hypothesis: where are we at. Neuroscientist. 2016;22:266–277. PubMed

Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med. 2001;344:710–719. PubMed

Fu M, St-Pierre P, Shankar J, Wang PT, Joshi B, Nabi IR. Regulation of mitophagy by the Gp78 E3 ubiquitin ligase. Mol Biol Cell. 2013;24:1153–1162. PubMed PMC

Fu Z, Tindall DJ. FOXOs, cancer and regulation of apoptosis. Oncogene. 2008;27:2312–2319. PubMed PMC

Fukui H, Moraes CT. Extended polyglutamine repeats trigger a feedback loop involving the mitochondrial complex III, the proteasome and huntingtin aggregates. Hum Mol Genet. 2007;16:783–797. PubMed

Funalot B, Desport JC, Sturtz F, Camu W, Couratier P. High metabolic level in patients with familial amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2009;10:113–117. PubMed

Galano A, Tan DX, Reiter RJ. Melatonin as a natural ally against oxidative stress: a physicochemical examination. J Pineal Res. 2011;51:1–16. PubMed

Gammage PA, Rorbach J, Vincent AI, Rebar EJ, Minczuk M. Mitochondrially targeted ZFNs for selective degradation of pathogenic mitochondrial genomes bearing large-scale deletions or point mutations. EMBO Mol Med. 2014;6:458–466. PubMed PMC

Gammage PA, Viscomi C, Simard ML, Costa ASH, Gaude E, Powell CA, Van Haute L, McCann BJ, Rebelo-Guiomar P, Cerutti R, Zhang L, Rebar EJ, Zeviani M, Frezza C, Stewart JB, Minczuk M. Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo. Nat Med. 2018;24:1691–1695. PubMed PMC

Ganeshan V, Skladnev NV, Kim JY, Mitrofanis J, Stone J, Johnstone DM. Pre-conditioning with remote photobiomodulation modulates the brain transcriptome and protects against MPTP insult in mice. Neuroscience. 2019;400:85–97. PubMed

Geisler JG, Marosi K, Halpern J, Mattson MP. DNP, mitochondrial uncoupling, and neuroprotection: A little dab’ll do ya. Alzheimers Dement. 2017;13:582–591. PubMed PMC

Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. 2010;12:119–131. PubMed

Gillette TG, Kumar B, Thompson D, Slaughter CA, DeMartino GN. Differential roles of the COOH termini of AAA subunits of PA700 (19 S regulator) in asymmetric assembly and activation of the 26 S proteasome. J Biol Chem. 2008;283:31813–31822. PubMed PMC

Giuliano P, De Cristofaro T, Affaitati A, Pizzulo GM, Feliciello A, Criscuolo C, De Michele G, Filla A, Avvedimento EV, Varrone S. DNA damage induced by polyglutamine-expanded proteins. Hum Mol Genet. 2003;12:2301–2309. PubMed

Gleyzer N, Vercauteren K, Scarpulla RC. Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Mol Cell Biol. 2005;25:1354–1366. PubMed PMC

Golpich M, Rahmani B, Mohamed Ibrahim N, Dargahi L, Mohamed Z, Raymond AA, Ahmadiani A. Preconditioning as a potential strategy for the prevention of Parkinson’s disease. Mol Neurobiol. 2015;51:313–330. PubMed

Golpich M, Amini E, Mohamed Z, Azman Ali R, Mohamed Ibrahim N, Ahmadiani A. Mitochondrial dysfunction and biogenesis in neurodegenerative diseases: pathogenesis and treatment. CNS Neurosci Ther. 2017;23:5–22. PubMed PMC

Gomes LC, Di Benedetto G, Scorrano L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol. 2011;13:589–598. PubMed PMC

Graziewicz MA, Longley MJ, Copeland WC. DNA polymerase gamma in mitochondrial DNA replication and repair. Chem Rev. 2006;106:383–405. PubMed

Greenamyre JT, Hastings TG. Parkinson’s: divergent causes, convergent mechanisms. Science. 2004;304:1120–1122. PubMed

Griparic L, Van Der Wel NN, Orozco IJ, Peters PJ, Van Der Bliek AM. Loss of the intermembrane space protein Mgm1/OPA1 induces swelling and localized constrictions along the lengths of mitochondria. J Biol Chem. 2004;279:18792–18798. PubMed

Guo X, Disatnik MH, Monbureau M, Shamloo M, Mochly-Rosen D, Qi X. Inhibition of mitochondrial fragmentation diminishes Huntington’s disease-associated neurodegeneration. J Clin Invest. 2013;123:5371–5388. PubMed PMC

Hamanaka RB, Chandel NS. Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends Biochem Sci. 2010;35:505–513. PubMed PMC

Handy DE, Loscalzo J. Redox regulation of mitochondrial function. Antioxid Redox Signal. 2012;16:1323–1367. PubMed PMC

Hansson Petersen CA, Alikhani N, Behbahani H, Wiehager B, Pavlov PF, Alafuzoff I, Leinonen V, Ito A, Winblad B, Glaser E, Ankarcrona M. The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc Natl Acad Sci U S A. 2008;105:13145–13150. PubMed PMC

Haun F, Nakamura T, Lipton SA. Dysfunctional mitochondrial dynamics in the pathophysiology of neurodegenerative diseases. J Cell Death. 2013;6:27–35. PubMed PMC

Hauptmann S, Scherping I, Dröse S, Brandt U, Schulz KL, Jendrach M, Leuner K, Eckert A, Müller WE. Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging. 2009;30:1574–1586. PubMed

Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C, Ji X, Lo EH. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016;535:551–555. PubMed PMC

Hennessy M, Hamblin MR. Photobiomodulation and the brain: a new paradigm. J Opt. 2017;19:013003. PubMed PMC

Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA. Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci. 2001;21:3017–3023. PubMed PMC

Höglinger GU, Carrard G, Michel PP, Medja F, Lombès A, Ruberg M, Friguet B, Hirsch EC. Dysfunction of mitochondrial complex I and the proteasome: interactions between two biochemical deficits in a cellular model of Parkinson’s disease. J Neurochem. 2003;86:1297–1307. PubMed

Hou Y, Dan X, Babbar M, Wei Y, Hasselbalch SG, Croteau DL, Bohr VA. Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol. 2019;15:565–581. PubMed

Huang L, Ho P, Chen CH. Activation and inhibition of the proteasome by betulinic acid and its derivatives. FEBS Lett. 2007;581:4955–4959. PubMed PMC

Hughes SD, Kanabus M, Anderson G, Hargreaves IP, Rutherford T, O’Donnell M, Cross JH, Rahman S, Eaton S, Heales SJ. The ketogenic diet component decanoic acid increases mitochondrial citrate synthase and complex I activity in neuronal cells. J Neurochem. 2014;129:426–433. PubMed

Iliev AI, Stringaris AK, Nau R, Neumann H. Neuronal injury mediated via stimulation of microglial toll-like receptor-9 (TLR9) FASEB J 18:412-414. 2004 PubMed

Illuzzi J, Yerkes S, Parekh-Olmedo H, Kmiec EB. DNA breakage and induction of DNA damage response proteins precede the appearance of visible mutant huntingtin aggregates. J Neurosci Res. 2009;87:733–747. PubMed

Innamorato NG, Lastres-Becker I, Cuadrado A. Role of microglial redox balance in modulation of neuroinflammation. Curr Opin Neurol. 2009;22:308–314. PubMed

Intlekofer KA, Cotman CW. Exercise counteracts declining hippocampal function in aging and Alzheimer’s disease. Neurobiol Dis. 2013;57:47–55. PubMed

Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S, Yamamoto M. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem. 2000;275:16023–16029. PubMed

Ito Y, Ofengeim D, Najafov A, Das S, Saberi S, Li Y, Hitomi J, Zhu H, Chen H, Mayo L, Geng J, Amin P, DeWitt JP, Mookhtiar AK, Florez M, Ouchida AT, Fan JB, Pasparakis M, Kelliher MA, Ravits J, et al. RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science. 2016;353:603–608. PubMed PMC

Itoh K, Nakamura K, Iijima M, Sesaki H. Mitochondrial dynamics in neurodegeneration. Trends Cell Biol. 2013;23:64–71. PubMed PMC

Iyer S, Thomas R, Portell F, Dunham L, Quigley C, Bennett J., Jr Recombinant mitochondrial transcription factor A with N-terminal mitochondrial transduction domain increases respiration and mitochondrial gene expression. Mitochondrion. 2009;9:196–203. PubMed PMC

Iyer S, Bergquist K, Young K, Gnaiger E, Rao RR, Bennett JP., Jr Mitochondrial gene therapy improves respiration, biogenesis, and transcription in G11778A Leber’s hereditary optic neuropathy and T8993G Leigh’s syndrome cells. Hum Gene Ther. 2012;23:647–657. PubMed PMC

Jäger S, Handschin C, St-Pierre J, Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC- 1alpha. Proc Natl Acad Sci U S A. 2007;104:12017–12022. PubMed PMC

Jain A, Lamark T, Sjøttem E, Larsen KB, Awuh JA, Øvervatn A, McMahon M, Hayes JD, Johansen T. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J Biol Chem. 2010;285:22576–22591. PubMed PMC

Jin H, Kanthasamy A, Ghosh A, Anantharam V, Kalyanaraman B, Kanthasamy A. Mitochondria-targeted antioxidants for treatment of Parkinson’s disease: preclinical and clinical outcomes. Biochim Biophys Acta. 2014;1842:1282–1294. PubMed PMC

Jin SM, Lazarou M, Wang C, Kane LA, Narendra DP, Youle RJ. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol. 2010;191:933–942. PubMed PMC

Jodeiri Farshbaf M, Ghaedi K, Megraw TL, Curtiss J, Shirani Faradonbeh M, Vaziri P, Nasr-Esfahani MH. Does PGC1α/FNDC5/BDNF elicit the beneficial effects of exercise on neurodegenerative disorders. Neuromolecular Med. 2016;18:1–15. PubMed

Jones CL, Tepe JJ. Proteasome activation to combat proteotoxicity. Molecules. 2019;24:2841. PubMed PMC

Jornayvaz FR, Shulman GI. Regulation of mitochondrial biogenesis. Essays Biochem. 2010;47:69–84. PubMed PMC

Joshi AU, Saw NL, Shamloo M, Mochly-Rosen D. Drp1/Fis1 interaction mediates mitochondrial dysfunction, bioenergetic failure and cognitive decline in Alzheimer’s disease. Oncotarget. 2017;9:6128–6143. PubMed PMC

Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW. Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest. 2004;113:1535–4910. PubMed PMC

Jung C, Higgins CMJ, Xu Z. Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis. J Neurochem. 2002;83:535–545. PubMed

Kageyama Y, Hoshijima M, Seo K, Bedja D, Sysa-Shah P, Andrabi SA, Chen W, Höke A, Dawson VL, Dawson TM, Gabrielson K, Kass DA, Iijima M, Sesaki H. Parkin-independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain. EMBO J. 2014;38:2798–2813. PubMed PMC

Kapetanovic R, Bokil NJ, Sweet MJ. Innate immune perturbations, accumulating DAMPs and inflammasome dysregulation: A ticking time bomb in ageing. Ageing Res Rev. 2015;24:40–53. PubMed

Karalija A, Novikova LN, Kingham PJ, Wiberg M, Novikov LN. Neuroprotective effects of N-acetyl-cysteine and acetyl-L-carnitine after spinal cord injury in adult rats. PLoS One 7. 2012:e41086. PubMed PMC

Karbowski M, Neutzner A. Neurodegeneration as a consequence of failed mitochondrial maintenance. Acta Neuropathol. 2012;123:157–171. PubMed

Keeney PM, Xie J, Capaldi RA, Bennett JP., Jr Parkinson’s disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci. 2006;26:5256–5264. PubMed PMC

Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007;47:89–116. PubMed

Keogh MJ, Chinnery PF. Mitochondrial DNA mutations in neurodegeneration. Biochim Biophys Acta. 2015;1847:1401–1411. PubMed

Khalil B, Liévens JC. Mitochondrial quality control in amyotrophic lateral sclerosis: towards a common pathway. Neural Regen Res. 2017;12:1052–1061. PubMed PMC

Khalil B, El Fissi N, Aouane A, Cabirol-Pol MJ, Rival T, Liévens JC. PINK1-induced mitophagy promotes neuroprotection in Huntington’s disease. Cell Death Dis 6. 2015:e1617. PubMed PMC

Kierdorf K, Prinz M. Factors regulating microglia activation. Front Cell Neurosci. 2013;7:44. PubMed PMC

Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13:132–141. PubMed PMC

Kim J, Moody JP, Edgerly CK, Bordiuk OL, Cormier K, Smith K, Beal MF, Ferrante RJ. Mitochondrial loss, dysfunction and altered dynamics in Huntington’s disease. Hum Mol Genet. 2010;19:3919–3935. PubMed PMC

Kim SU, Lee HJ, Kim YB. Neural stem cell-based treatment for neurodegenerative diseases. Neuropathology. 2013;33:491–504. PubMed

Kish SJ, Bergeron C, Rajput A, Dozic S, Mastrogiacomo F, Chang LJ, Wilson JM, DiStefano LM, Nobrega JN. Brain cytochrome oxidase in Alzheimer’s disease. J Neurochem. 1992;59:776–779. PubMed

Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E. Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci. 2008;9:505–518. PubMed PMC

Kodavati M, Wang H, Hegde ML. Altered mitochondrial dynamics in motor neuron disease: an emerging perspective. Cells. 2020;9:1065. PubMed PMC

Koo JH, Kang EB, Kwon IS, Jang YC, Kim EJ, Lee Y, Cho IH, Cho JY. Endurance exercise confers neuroprotective mitochondrial phenotypes in the brain of Alzheimer’s disease mice. FASEB J. 2015;29:1055–1035.

Kops GJ, Dansen TB, Polderman E, Saarloos I, Wirtz KWA, Coffer PJ. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature. 2002;419:316–321. PubMed

Korecka JA, Eggers R, Swaab DF, Bossers K, Verhaagen J. Modeling early Parkinson’s disease pathology with chronic low dose MPTP treatment. Restor Neurol Neurosci. 2013;31:155–167. PubMed

Koshiba T, Detmer SA, Kaiser JT, Chen H, McCaffery JM, Chan DC. Structural basis of mitochondrial tethering by mitofusin complexes. Science. 2004;305:858–862. PubMed

Kubli DA, Gustafsson ÅB. Mitochondria and mitophagy: The yin and yang of cell death control. Circ Res. 2012;111:1208–1221. PubMed PMC

Kuljis RO, Xu Y, Aguila MC, Baltimore D. Degeneration of neurons, synapses, and neuropil and glial activation in a murine ATM knockout model of Ataxia-telangiectasia. Proc Natl Acad Sci U S A. 1997;94:12688–12693. PubMed PMC

Kumar S, Bharti A, Mishra NC, Raina D, Kharbanda S, Saxena S. Targeting of the c-Abl tyrosine kinase to mitochondria in the necrotic cell death response to oxidative stress. J Biol Chem. 2001;276:17281–17510. PubMed

Kurz T, Terman A, Brunk UT. Autophagy, ageing and apoptosis: the role of oxidative stress and lysosomal iron. Arch Biochem Biophys. 2007;462:220–230. PubMed

Kwak MK, Wakabayashi N, Greenlaw JL, Yamamoto M, Kensler TW. Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Mol Cell Biol. 2003;23:8786–8794. PubMed PMC

Lau JL, Dunn MK. Therapeutic peptides: Historical perspectives, current development trends, and future directions. Bioorg Med Chem. 2018;26:2700–2707. PubMed

Lee BH, Lee MJ, Park S, Oh DC, Elsasser S, Chen PC, Gartner C, Dimova N, Hanna J, Gygi SP, Wilson SM, King RW, Finley D. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature. 2010;467:179–184. PubMed PMC

Lee J, Kosaras B, Del Signore SJ, Cormier K, McKee A, Ratan RR, Kowall NW, Ryu H. Modulation of lipid peroxidation and mitochondrial function improves neuropathology in Huntington’s disease mice. Acta Neuropathol. 2011;121:487–498. PubMed PMC

Lee J KM, Ferrante RJ, Kowall NW, Ryu H. Activation of Ets-2 by oxidative stress induces Bcl-xL expression and accounts for glial survival in amyotrophic lateral sclerosis. FASEB J. 2009;23:1739–1749. PubMed PMC

Lee JY, Nagano Y, Taylor JP, Lim KL, Yao TP. Disease-causing mutations in Parkin impair mitochondrial ubiquitination, aggregation, and HDAC6- dependent mitophagy. J Cell Biol. 2010a;189:671–679. PubMed PMC

Lee JY, Koga H, Kawaguchi Y, Tang W, Wong E, Gao YS. HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J. 2010b;29:969–980. PubMed PMC

Leestemaker Y, de Jong A, Witting KF, Penning R, Schuurman K, Rodenko B, Zaal EA, van de Kooij B, Laufer S, Heck AJR, Borst J, Scheper W, Berkers CR, Ovaa H. Proteasome Activation by Small Molecules. Cell Chem Biol. 2017;24:725–736. PubMed

Lemasters J. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res. 2005;8:3–5. PubMed

Lewis TL, Kwon SK, Lee A, Shaw R, Polleux F. MFF-dependent mitochondrial fission regulates presynaptic release and axon branching by limiting axonal mitochondria size. Nat Commun. 2018;9:5008. PubMed PMC

Li Z, Okamoto KI, Hayashi Y, Sheng M. The Importance of Dendritic Mitochondria in the Morphogenesis and Plasticity of Spines and Synapses. Cell. 2004;119:873–887. PubMed

Licastro F, Pedrini S, Caputo L, Annoni G, Davis LJ, Ferri C, Casadei V, Grimaldi LM. Increased plasma levels of interleukin-1, interleukin-6 and alpha-1-antichymotrypsin in patients with Alzheimer’s disease: Peripheral inflammation or signals from the brain. J Neuroimmunol. 2000;103:97–102. PubMed

Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006;443:787–795. PubMed

Liu L, Feng D, Chen G, Chen M, Zheng Q, Song P, Ma Q Q, Zhu C, Wang R, Qi W. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol. 2012;14:177–185. PubMed

Liu N, Stoica G, Yan M, Scofield VL, Qiang W, Lynn WS, Wong PK. ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes. Lab Investig. 2005;85:1471–1480. PubMed

Liu W, Yamashita T, Tian F, Morimoto N, Ikeda Y, Deguchi K, Abe K. Mitochondrial fusion and fission proteins expression dynamically change in a murine model of amyotrophic lateral sclerosis. Curr Neurovasc Res. 2013;10:222–230. PubMed

Livigni A, Scorziello A, Agnese S, Adornetto A, Carlucci A, Garbi C. Mitochondrial AKAP121 links cAMP and src signaling to oxidative metabolism. Mol Biol Cell. 2006;17:263–271. PubMed PMC

Lo AC, Callaerts-Vegh Z, Nũnes AF, Rodrigues CM, D’Hooge R. Tauroursodeoxycholic acid (TUDCA) supplementation prevents cognitive impairment and amyloid deposition in APP/PS1 mice. Neurobiol Dis. 2013;50:21–29. PubMed

Lokireddy S, Wijesoma IW, Teng S, Bonala S, Gluckman PD, McFarlane C, Sharma M, Kambadur R. The ubiquitin ligase Mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli. Cell Metab. 2012;16:613–624. PubMed

Loson OC, Song Z, Chen H, Chan DC. Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell. 2013;24:659–667. PubMed PMC

Louneva N, Cohen JW, Han LY, Talbot K, Wilson RS, Bennett DA, Trojanowski JQ, SE A. Caspase-3 is enriched in postsynaptic densities and increased in Alzheimer’s disease. Am J Pathol. 2008;173:1488–1495. PubMed PMC

Luo S, Valencia CA, Zhang J, Lee NC, Slone J, Gui B, Wang X, Li Z, Dell S, Brown J, Chen SM, Chien YH, Hwu WL, Fan PC, Wong LJ, Atwal PS, Huang T. Biparental Inheritance of Mitochondrial DNA in Humans. Proc Natl Acad Sci U S A. 2018;115:13039–13044. PubMed PMC

Luth ES, Stavrovskaya IG, Bartels T, Kristal BS, Selkoe DJ. Soluble, prefibrillar α-synuclein oligomers promote complex I-dependent, Ca2+-induced mitochondrial dysfunction. J Biol Chem. 2014;289:21490–21507. PubMed PMC

Maijenburg MW, van der Schoot CE, Voermans C. Mesenchymal stromal cell migration: possibilities to improve cellular therapy. Stem Cells Dev. 2012;21:19–29. PubMed

Majumder PK, Mishra NC, Sun X, Bharti A, Kharbanda S, Saxena S, Kufe D. Targeting of protein kinase C delta to mitochondria in the oxidative stress response. Cell Growth Differ. 2001;12:465–470. PubMed

Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996;87:493–506. PubMed

Martel C, Allouche M, Esposti DD, Fanelli E, Boursier C, Henry C. Glycogen synthase kinase 3-mediated voltage-dependent anion channel phosphorylation controls outer mitochondrial membrane permeability during lipid accumulation. Hepatology. 2013;57:93–102. PubMed

Mattson MP, Arumugam TV. Hallmarks of brain aging: adaptive and pathological modification by metabolic states. Cell Metabolism. 2018;27:1176–1199. PubMed PMC

Maurer U, Chavret C, Wagman AS, Dejardin E, Green DR. Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell. 2006;21:749–760. PubMed

McCarroll SA, Murphy CT, Zou S, Pletcher SD, Chin CS, Jan YN, Kenyon C, Bargmann CI, Li H. Comparing genomic expression patterns across species identifies shared transcriptional profile in aging. Nat Genet. 2004;36:197–204. PubMed

Mendivil-Perez M, Soto-Mercado V, Guerra-Librero A, Fernandez-Gil BI, Florido J, Shen YQ, Tejada MA, Capilla-Gonzalez V, Rusanova I, Garcia-Verdugo JM, Acuña-Castroviejo D, López LC, Velez-Pardo C, Jimenez-Del-Rio M, Ferrer JM, Escames G. Melatonin enhances neural stem cell differentiation and engraftment by increasing mitochondrial function. J Pineal Res. 2017 doi: 101111/jpi12415. PubMed

Menzies FM, Cookson MR, Taylor RW, Turnbull DM, Chrzanowska-Lightowlers ZM, Dong L, Figlewicz DA, Shaw PJ. Mitochondrial dysfunction in a cell culture model of familial amyotrophic lateral sclerosis. Brain. 2002;125(Pt 7):1522–1533. PubMed

Metodiev MD, Lesko N, Park CB, Cámara Y, Shi Y, Wibom R, Hultenby K, Gustafsson CM, Larsson NG. Methylation of 12S rRNA is necessary for in vivo stability of the small subunit of the mammalian mitochondrial ribosome. Cell Metab. 2009;9:386–397. PubMed

Mihaylova MM, Shaw RJ. The AMPK signaling pathway coordinates cell growth, autophagy and metabolism. Nat Rev Cell Biol. 2011;13:1016–1023. PubMed PMC

Miyazaki T, Neff L, Tanaka S, Horne WC, Baron R. Regulation of cytochrome c oxidase activity by c-Src in osteoclasts. J Cell Biol. 2003;160:709–718. PubMed PMC

Morciano G, Pedriali G, Sbano L, Iannitti T, Giorgi C, Pinton P. Intersection of mitochondrial fission and fusion machinery with apoptotic pathways: Role of Mcl-1. Biol Cell. 2016;108:279–293. PubMed

Murphy MP, Holmgren A, Larsson NG, Halliwell B, Chang CJ, Kalyanaraman B, Rhee SG, Thornalley PJ, Partridge L, Gems D, Nystrom T, Belousov V, Schumacker PT, Winterbourn CC. Unraveling the biological roles of reactive oxygen species. Cell Metab. 2011;13:361–366. PubMed PMC

Mutisya EM, Bowling AC, Beal MF. Cortical cytochrome oxidase activity is reduced in Alzheimer’s disease. J Neurochem. 1994;63:2179–2184. PubMed

Myeku N, Clelland CL, Emrani S, Kukushkin NV, Yu WH, Goldberg AL, Duff KE. Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nat Med. 2016;22:46–53. PubMed PMC

Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, Fitzgerald KA, Ryter SW, Choi AM. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;12:222–230. PubMed PMC

Nakamura K, Nemani VM, Wallender EK, Kaehlcke K, Ott M, Edwards RH. Optical reporters for the conformation of alpha-synuclein reveal a specific interaction with mitochondria. J Neurosci. 2008;28:12305–12317. PubMed PMC

Nakamura T, Cieplak P, Cho DH, Godzik A, Lipton SA. S-nitrosylation of Drp1 links excessive mitochondrial fission to neuronal injury in neurodegeneration. Mitochondrion. 2010;10:573–578. PubMed PMC

Narendra D, Tanaka A, Suen D-F, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008;183:795–803. PubMed PMC

Narendra D, Kane LA, Hauser DN, Fearnley IM, Youle RJ. p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy. 2010;6:1090–1106. PubMed PMC

Narendra DP, Youle RJ. Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control. Antioxid Redox Signal. 2011;14:1929–1938. PubMed PMC

Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8. 2010:e1000298. PubMed PMC

Naudi A, Jove M, Ayala V, Cassanye A, Serrano J, Gonzalo H, Boada J, Prat J, Portero-Otin M, Pamplona R. Cellular dysfunction in diabetes as maladaptive response to mitochondrial oxidative stress. Exp Diabetes Res. 2012;2012:696215. PubMed PMC

Naue J, Horer S, Sanger T. Evidence for frequent and tissue-specific sequence heteroplasmy in human mitochondrial DNA. Mitochondrion. 2015;20:82–94. PubMed

Nehilla BJ, Bergkvist M, Popat KC, Desai TA. Purified and surfactant-free coenzyme Q10-loaded biodegradable nanoparticles. Int J Pharm. 2008;348(1-2):107–114. PubMed

Neuspiel M, Zunino R, Gangaraju S, Rippstein P, McBride H. Activated mitofusin 2 signals mitochondrial fusion, interferes with Bax activation, and reduces susceptibility to radical induced depolarization. J Biol Chem. 2005;280:25060–25070. PubMed

Newell C, Sabouny R, Hittel DS, Shutt TE, Khan A, Klein MS, Shearer J. Mesenchymal stem cells shift mitochondrial dynamics and enhance oxidative phosphorylation in recipient cells. Front Physiol. 2018;13:1572. PubMed PMC

Ng CH, Guan MS, Koh C, Ouyang X, Yu F, Tan EK, O’Neill SP, Zhang X, Chung J, Lim KL. AMP kinase activation mitigates dopaminergic dysfunction and mitochondrial abnormalities in Drosophila models of Parkinson’s disease. J Neurosci. 2012;32:14311–14317. PubMed PMC

Novak I, Kirkin V, McEwan DG, Zhang J, Wild P, Rozenknop A, Rogov V, Löhr F, Popovic D, Occhipinti A, Reichert AS, Terzic J, Dötsch V, Ney PA, Dikic I. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep. 2010;11:45–51. PubMed PMC

Nunes AF, Amaral JD, Lo AC, Fonseca MB, Viana RJ, Callaerts-Vegh Z, D’Hooge R, Rodrigues CM. TUDCA, a bile acid, attenuates amyloid precursor protein processing and amyloid-β deposition in APP/PS1 mice. Mol Neurobiol. 2012;45:440–454. PubMed

Olichon A, Baricault L, Gas N, Guillou E, Valette A, Belenguer P, Lenaers G. Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem. 2003;278:7743–7746. PubMed

Onyango IG, Lu J, Rodova M, Lezi E, Crafter AB, Swerdlow RH. Regulation of neuron mitochondrial biogenesis and relevance to brain health. Biochim Biophys Acta. 2010;1802:228–234. PubMed

Orsini M, Oliveira AB, Nascimento OJ, Reis CH, Leite MA, de Souza JA, Pupe C, de Souza OG, Bastos VH, de Freitas MR, Teixeira S, Bruno C, Davidovich E, Smidt B. Amyotrophic lateral sclerosis: new perpectives and update. Neurol Int. 2015;7:5885. PubMed PMC

Ortega-Arellano HF, Jimenez-Del-Rio M, Velez-Pardo C. Life span and locomotor activity modification by glucose and polyphenols in Drosophila melanogaster chronically exposed to oxidative stress-stimuli: implications in Parkinson’s disease. Neurochem Res. 2011;36:1073–1086. PubMed

Outeiro TF, Putcha P, Tetzlaff JE, Spoelgen R, Koker M, Carvalho F, Hyman BT, McLean PJ. Formation of toxic oligomeric alpha- synuclein species in living cells. PLoS One 3. 2008:e1867. PubMed PMC

Oyewole AO, Birch-Machin MA. Mitochondria-targeted antioxidants. FASEB J. 2015;29:4766–4771. PubMed

Paillard T, Rolland Y, de Souto Barreto P. Protective effects of physical exercise in alzheimer’s disease and parkinson’s disease: a narrative review. J Clin Neurol. 2015;11:212–219. PubMed PMC

Palmer CS, Osellame LD, Laine D, Koutsopoulos OS, Frazier AE, Ryan MT. MiD49 and MiD51, new components of the mitochondrial fission machinery. EMBO Rep. 2011;12:565–573. PubMed PMC

Palmer CS, Elgass KD, Parton RG, Osellame LD, Stojanovski D, Ryan MT. Adaptor proteins MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment and are specific for mitochondrial fission. J Biol Chem. 2013;288:27584–27593. PubMed PMC

Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Øvervatn A, Bjørkøy G, Johansen T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007;282:24131–24145. PubMed

Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D, Brown RH., Jr Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron. 2004;43:19–30. PubMed

Patel SP, Sullivan PG, Lyttle TS, Rabchevsky AG. Acetyl-L-carnitine ameliorates mitochondrial dysfunction following contusion spinal cord injury. J Neurochem. 2010;114:291–301. PubMed PMC

Patel SP, Sullivan PG, Lyttle TS, Magnuson DSK, Rabchevsky AG. Acetyl-L-carnitine treatment following spinal cord injury improves mitochondrial function correlated with remarkable tissue sparing and functional recovery. Neuroscience. 2012;210:296–307. PubMed PMC

Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology. 2002;36:525–531. PubMed

Peeva V, Blei D, Trombly G, Corsi S, Szukszto MJ, Rebelo-Guiomar P, Gammage PA, Kudin AP, Becker C, Altmüller J, Minczuk M, Zsurka G, Kunz WS. Linear mitochondrial DNA is rapidly degraded by components of the replication machinery. Nat Commun. 2018;9:1727. PubMed PMC

Perales-Clemente E, Bayona-Bafaluy MP, Perez-Martos A, Barrientos A, Fernandez-Silva P, Enriquez JA. Restoration of electron transport without proton pumping in mammalian mitochondria. Proc Natl Acad Sci U S A. 2008;105:18735–18739. PubMed PMC

Pereira CV, Bacman SR, Arguello T, Zekonyte U, Williams SL, Edgell DR, Moraes CT. mitoTev-TALE: a monomeric DNA editing enzyme to reduce mutant mitochondrial DNA levels. EMBO Mol Med 10. 2018:e8084. PubMed PMC

Perez-Severiano F, Santamaria A, Pedraza-Chaverri J, MedinaCampos ON, Rios C, Segovia J. Increased formation of reactive oxygen species, but no changes in glutathione peroxidase activity, in striata of mice transgenic for the Huntington’s disease mutation. Neurochem Res. 2004;29:729–733. PubMed

Petersen AJ, Rimkus SA, Wassarman DA. ATM kinase inhibition in glial cells activates the innate immune response and causes neurodegeneration in Drosophila. Proc Natl Acad Sci U S A. 2012;109:E656–664. PubMed PMC

Pettegrew JW, Levine J, McClure RJ. Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer’s disease and geriatric depression. Mol Psychiatry. 2000;5:616–632. PubMed

Picca A, Fracasso F, Pesce V, Cantatore P, Joseph AM, Leeuwenburgh C, Gadaleta MN, Lezza AM. Age- and calorie restriction-related changes in rat brain mitochondrial DNA and TFAM binding. Age (Dordr) 2013;35:1607–1620. PubMed PMC

Pickrell AM, Youle RJ. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron. 2015;85:257–273. PubMed PMC

Pieczenik SR, Neustadt J. Mitochondrial dysfunction and molecular pathways of disease. Exp Mol Pathol. 2007;83:84–92. PubMed

Piermarocchi S, Saviano S, Parisi V, Tedeschi M, Panozzo G, Scarpa G, Boschi G, Lo Giudice G Carmis Study Group. Carotenoids in Age-related Maculopathy Italian Study (CARMIS): two-year results of a randomized study. Eur J Ophthalmol. 2012;22:216–225. PubMed

Pivovarova NB, Andrews SB. Calcium-dependent mitochondrial function and dysfunction in neurons. FEBS J. 2010;277:3622–3636. PubMed PMC

Pollari E, Goldsteins G, Bart G, Koistinaho J, Giniatullin R. The role of oxidative stress in degeneration of the neuromuscular junction in amyotrophic lateral sclerosis. Front Cell Neurosci. 2014;8:131. PubMed PMC

Pradat PF, Bruneteau G, Gordon PH, Dupuis L, Bonnefont-Rousselot D, Simon D, Salachas F, Corcia P, Frochot V, Lacorte JM, Jardel C, Coussieu C, Le Forestier N, Lacomblez L, Loeffler JP, Meininger V. Impaired glucose tolerance in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2010;11:166–171. PubMed

Prior M, Dargusch R, Ehren JL, Chiruta C, Schubert D. The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer’s disease mice. Alzheimers Res Ther. 2013;5:25. PubMed PMC

Qin W, Haroutunian V, Katsel P, Cardozo CP, Ho L, Buxbaum JD, Pasinetti GM. PGC-1α expression decreases in the Alzheimer disease brain as a function of dementia. Arch Neurol. 2009;66:352–361. PubMed PMC

Quintanilla RA, Jin YN, Fuenzalida K, Bronfman M, Johnson GV. Rosiglitazone treatment prevents mitochondrial dysfunction in mutant Huntingtin-expressing cells possible role of peroxisome proliferator-activated receptor-γ (PPARγ ) in the pathogenesis of Huntington disease. J Biol Chem. 2008;283:25628–25637. PubMed PMC

Radak Z Z, Suzuki K, Higuchi M, Balogh L, Boldogh I, Koltai E. Physical exercise, reactive oxygen species and neuroprotection. Free Radic Biol Med. 2016;98:187–196. PubMed

Rai PK, Craven L, Hoogewijs K, Russell OM, Lightowlers RN. Advances in methods for reducing mitochondrial DNA disease by replacing or manipulating the mitochondrial genome. Essays Biochem. 2018;62:455–465. PubMed PMC

Ramalho RM, Borralho PM, Castro RE, Solá S, Steer CJ, Rodrigues CM. Tauroursodeoxycholic acid modulates p53-mediated apoptosis in Alzheimer’s disease mutant neuroblastoma cells. J Neurochem. 2006;98:1610–1618. PubMed

Rasola A, Bernardi P. Mitochondrial permeability transition in Ca2+-dependent apoptosis and necrosis. Cell Calcium. 2011;50:222–233. PubMed

Rebec GV, Barton SJ, Ennis MD. Dysregulation of ascorbate release in the striatum of behaving mice expressing the Huntington’s disease gene. J Neurosci. 2002;22:RC202. PubMed PMC

Rebelo AP, Dillon LM, Moraes CT. Mitochondrial DNA transcription regulation and nucleoid organization. J Inherit Metab Dis. 2011;34:941–951. PubMed

Reddy PH. Increased mitochondrial fission and neuronal dysfunction in Huntington’s disease: implications for molecular inhibitors of excessive mitochondrial fission. Drug Discov Today. 2014;19:951–955. PubMed PMC

Reddy PH. Role of mitochondria in neurodegenerative diseases: mitochondria as a therapeutic target in Alzheimer’s disease. CNS Spectr. 2009;14:8–13. PubMed PMC

Reddy PH, Mao P, Manczak M. Mitochondrial structural and functional dynamics in Huntington’s disease. Brain Res Rev. 2009;60:33–48. PubMed PMC

Reiter R, Tang L, Garcia JJ, Muñoz-Hoyos A. Pharmacological actions of melatonin in oxygen radical pathophysiology. Life Sci. 1997;60:2255–2271. PubMed

Reiter RJ, Tan DX, Galano A. Melatonin: exceeding expectations. Physiology (Bethesda) 2014;29:325–333. PubMed

Reiter RJ, Tan D, Kim SJ, Manchester LC, Qi W, Garcia JJ, Cabrera JC, El-Sokkary G, Rouvier-Garay V. Augmentation of indices of oxidative damage in life-long melatonin-deficient rats. Mech Ageing Dev. 1999;110:157–173. PubMed

Ressmeyer AR, Mayo JC, Zelosko V, Sáinz RM, Tan DX, Poeggeler B, Antolín I, Zsizsik BK, Reiter RJ, Hardeland R. Antioxidant properties of the melatonin metabolite N1-acetyl-5-methoxykynuramine (AMK): scavenging of free radicals and prevention of protein destruction. Redox Rep. 2003;8:205–213. PubMed

Reyes ET, Perurena OH, Festoff BW, Jorgensen R, Moore WV. Insulin resistance in amyotrophic lateral sclerosis. J Neurol Sci. 1984;63:317–324. PubMed

Rho JM, Rogawski MA. The ketogenic diet: stoking the powerhouse of the cell. Epilepsy Curr. 2007;7:58–60. PubMed PMC

Rimkus SA, Katzenberger RJ, Trinh AT, Dodson GE, Tibbetts RS, Wassarman DA. Mutations in String/CDC25 inhibit cell cycle re-entry and neurodegeneration in a Drosophila model of Ataxia telangiectasia. Genes Dev. 2008;22:1205–1220. PubMed PMC

Rizzuto R, De Stefani D, Raffaello A, Mammucar C. Mitochondria as sensors and regulators of calcium signalling. Nat Rev. 2012;2012:566–578. PubMed

Robey RB, Hay N. Is Akt the “Warburg kinase”– Akt energy metabolism interactions and oncogenesis. Semin Cancer Biol. 2009;19:25–31. PubMed PMC

Rojo AI, McBean G, Cindric M, Egea J, Lopez MG, Rada P, Zarkovic N, Cuadrado A. Redox control of microglial function: Molecular mechanisms and functional significance. Antioxid Redox Signal. 2014;21:1766–1801. PubMed PMC

Ross JM, Stewart JB, Hagström E, Brené S, Mourier A, Coppotelli G, Freyer C, Lagouge M, Hoffer BJ, Olson L, Larsson NG. Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature. 2013;501:412–415. PubMed PMC

Rossi S, Zanier ER, Mauri I, Columbo A, Stocchetti N. Brain temperature, body core temperature, and intracranial pressure in acute cerebral damage. J Neurol Neurosurg Psychiatry. 2001;71:448–454. PubMed PMC

Rothstein JD, Martin LJ, Kuncl RW. Decreased glutamate transport by the brain and spinal-cord in amyotrophic lateral sclerosis. N Engl J Med. 1992;326:1464–1468. PubMed

Rubinfeld B, Albert I, Porfiri E E, Fiol C, Munemitsu S, Polakis P. Binding of GSK3B to the APC-b-catenin complex and regulation of complex assembly. Science. 1996;272:1023–1610. PubMed

Russell AP, Wada S, Vergani L, Hock MB, Lamon S, Léger B, Ushida T, Cartoni R, Wadley GD, Hespel P, Kralli A, Soraru G, Angelini C, Akimoto T. Disruption of skeletal muscle mitochondrial network genes and miRNAs in amyotrophic lateral sclerosis. Neurobiol Dis. 2013;49:107–117. PubMed

Ryan MT, Hoogenraad NJ. Mitochondrial-nuclear communications. Annu Rev Biochem. 2007;76:701–722. PubMed

Saha RN, Pahan K. Regulation of inducible nitric oxide synthase gene in glial cells. Antioxid Redox Signal. 2006;8(5-6):929–947. PubMed PMC

Salehpour F, Mahmoudi J, Kamari F, Sadigh-Eteghad S, Rasta SH, Hamblin MR. Brain photobiomodulation therapy: a narrative review. Mol Neurobiol. 2018;55:6601–6636. PubMed PMC

Santamaría A, Pérez-Severiano F, Rodríguez-Martínez E, Maldonado PD, Pedraza-Chaverri J, Ríos C, Segovia J. Comparative analysis of superoxide dismutase activity between acute pharmacological models and a transgenic mouse model of Huntington’s disease. Neurochem Res. 2001;26:419–424. PubMed

Santos D, Cardoso SM. Mitochondrial dynamics and neuronal fate in Parkinson’s disease. Mitochondrion. 2012;12:428–437. PubMed

Santra S, Gilkerson RW, M D, Schon EA. Ketogenic treatment reduces deleted mitochondrial DNAs in cultured human cells. Ann Neurol. 2004;56:662–669. PubMed

Sanz-Blasco S, Valero RA, Rodríguez-Crespo I, Villalobos C, Núñez L. Mitochondrial Ca2+ overload underlies Aβ oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs. PLoS One 3. 2008:e2718. PubMed PMC

Sanz A, Soikkeli M, Portero-Otín M, Wilson A, Kemppainen E, McIlroy G, Ellilä S, Kemppainen KK, Tuomela T, Lakanmaa M, Kiviranta E, Stefanatos R, Dufour E, Hutz B, Naudí A, Jové M, Zeb A, Vartiainen S, Matsuno-Yagi A, Yagi T, et al. Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction. Proc Natl Acad Sci U S A. 2010;107:9105–9110. PubMed PMC

Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev. 2008;88:611–638. PubMed

Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol. 2008;7:97–109. PubMed

Schulz JB, Matthews RT, Beal MF. Role of nitric oxide in neurodegenerative diseases. Curr Opin Neurol. 1995;8:480–486. PubMed

Sebastián D, Palacín M, Zorzano A. Mitochondrial dynamics: coupling mitochondrial fitness with healthy aging. Trends Mol. 2017;23:201–215. PubMed

Sena LA, Chandel NS. Physiological roles of mitochondrial reactive oxygen species. Mol Cell. 2012;48:158–167. PubMed PMC

Shen X, Chen J, Li J, Kofler J, Herrup K. Neurons in vulnerable regions of the Alzheimer’s disease brain display reduced ATM signaling. eNeuro. 2016;3:ENEURO0124–152016. PubMed PMC

Sheng B, Wang X, Su B, Lee HG, Casadesus G, Perry G, Zhu X. Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer’s disease. J Neurochem. 2012;120:419–429. PubMed PMC

Shin JH, Ko HS, Kang H, Lee Y LY, Pletinkova O, Troconso JC, Dawson VL, Dawson TM. PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson’s disease. Cell. 2011;144:689–702. PubMed PMC

Shirendeb U, Reddy AP, Manczak M, Calkins MJ, Mao P, Tagle DA, Reddy PH. Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington’s disease: implications for selective neuronal damage. Hum Mol Genet. 2011;20:1438–1455. PubMed PMC

Shirendeb UP, Calkins MJ, Manczak M, Anekonda V, Dufour B, McBride JL, Mao P, Reddy PH. Mutant huntingtin’s interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington’s disease. Hum Mol Genet. 2012;21:406–420. PubMed PMC

Smith RA, Murphy MP. Mitochondria-targeted antioxidants as therapies. Discov Med. 2011;11:106–114. PubMed

Song W, Song Y, Kincaid B BB, Bossy-Wetzel E. Mutant SOD1G93A triggers mitochondrial fragmentation in spinal cord motor neurons: Neuroprotection by SIRT3 and PGC-1α. Neurobiol Dis. 2013;51:72–81. PubMed PMC

Song YM, Lee YH, Kim JW, Ham DS, Kang ES, Cha BS, Lee HC, Lee BW. Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway. Autophagy. 2015;11:46–59. PubMed PMC

Stack EC, Matson WR, Ferrante RJ. Evidence of oxidant damage in Huntington’s disease: translational strategies using antioxidants. Ann N Y Acad Sci. 2008;1147:79–92. PubMed

Stetler RA, Leak R, Gao Y, Chen J. The dynamics of the mitochondrial organelle as a potential therapeutic organelle. J Cereb Blood Flow Metab. 2013;33:22–32. PubMed PMC

Stewart JB, Larsson NG. Keeping mtDNA in shape between generations. PLoS Genet. 2014;10:10. PubMed PMC

Stewart JB, Chinnery PF. The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat Rev Genet. 2015;16:530–542. PubMed

Surmeier DJ. Calcium, ageing, and neuronal vulnerability in Parkinson’s disease. Lancet. 2007;6:933–938. PubMed

Swerdlow RH, Parks JK, Cassarino DS, Maguire DJ, Maguire RS, Bennett JP, Jr, Davis RE, Parker WD., Jr Cybrids in Alzheimer’s disease: a cellular model of the disease. Neurology. 1997;49:918–925. PubMed

Tan DX, Manchester LC, Burkhardt S, Sainz RM, Mayo JC, Kohen R, Shohami E, Huo YS, Hardeland R, RJ R. N1-acetyl-N2-formyl-5-methoxykynuramine, a biogenic amine and melatonin metabolite, functions as a potent antioxidant. FASEB J. 2001;15:2294–2296. PubMed

Tan DX, Reiter RJ, Manchester LC, Yan MT, El-Sawi M, Sainz RM, Mayo JC, Kohen R, Allegra M, R. H Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem. 2002;2:181–197. PubMed

Tanaka A, Cleland MM, Xu S, Narendra DP, Suen DF, Karbowski M, Youle RJ. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol. 2010;191:1367–1380. PubMed PMC

Tasset I, Sanchez F, Tunez I. The molecular bases of Huntington’s disease: the role played by oxidative stress. Rev Neurol. 2009;49:424–429. PubMed

Thau N, Knippenberg S, Körner S, Rath KJ, Dengler R, Petri S. Decreased mRNA expression of PGC-1α and PGC-1α-regulated factors in the SOD1G93A ALS mouse model and in human sporadic ALS. J Neuropathol Exp Neurol. 2012;71:1064–1074. PubMed

Thomas RR, Khan SM, Smigrodzki RM, Onyango IG, Dennis J, Khan OM, Portell FR, Bennett JP. RhTFAM treatment stimulates mitochondrial oxidative metabolism and improves memory in aged mice. Aging (Albany NY) 2012;4:620–635. PubMed PMC

Tibaldi E, Brunati AM, Massimino ML, Stringaro A, Colone M, Agostinelli E, Arancia G, Toninello A. Src-Tyrosine kinases are major agents in mitochondrial tyrosine phosphorylation. J Cell Biochem. 2008;104:840–910. PubMed

Tilokani L, Nagashima S, Paupe V, Prudent J. Mitochondrial dynamics: overview of molecular mechanisms. Essays Biochem. 2018;62:341–360. PubMed PMC

Tiranti V, Savoia A, Forti F, D’Apolito MF, Centra M, Rocchi M, Zeviani M. Identification of the gene encoding the human mitochondrial RNA polymerase (h-mtRPOL) by cyberscreening of the Expressed Sequence Tags database. Hum Mol Genet. 1997;6:615–625. PubMed

Tomiyama H, Mizuta I, Li Y, Funayama M, Yoshino H, Li L, Murata M, Yamamoto M, Kubo SI, Mizuno Y, Toda T, Hattori N. LRRK2 P755L variant in sporadic Parkinson’s disease. J Hum Genet. 2008;53(11-12):1012–1015. PubMed

Tradewell ML, Cooper LA, Minotti S, Durham HD. Calcium dysregulation, mitochondrial pathology and protein aggregation in a culture model of amyotrophic lateral sclerosis: Mechanistic relationship and differential sensitivity to intervention. Neurobiol Dis. 2011;42:265–275. PubMed

Trimmer PA, Bennett JP., Jr The cybrid model of sporadic Parkinson’s disease. Exp Neurol. 2009;218:320–325. PubMed PMC

Trimmer PA, Keeney PM, Borland MK, Simon FA, Almeida J, Swerdlow RH, Parks JP, Parker WD, Jr, Bennett JP., Jr Mitochondrial abnormalities in cybrid cell models of sporadic Alzheimer’s disease worsen with passage in culture. Neurobiol Dis. 2004;15:29–39. PubMed

Trippier PC, Zhao KT, Fox SG, Schiefer IT, Benmohamed R, Moran J, Kirsch DR, Morimoto RI, Silverman RB. Proteasome activation is a mechanism for pyrazolone small molecules displaying therapeutic potential in amyotrophic lateral sclerosis ACS Chem Neurosci 5:823-829. 2014 PubMed PMC

Tsunemi T, La Spada AR. PGC-1α at the intersection of bioenergetics regulation and neuronal function: From Huntington’s disease to Parkinson’s disease and beyond. Prog Neurobiol. 2012;97:142–151. PubMed PMC

Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. Embo J. 2008;27:433–446. PubMed PMC

Uittenbogaard M, Chiaramello A. Mitochondrial biogenesis: A therapeutic target for neurodevelopmental disorders and neurodegenerative diseases. Curr Pharm Des. 2014;20:5574–5559. PubMed PMC

Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science. 2004;304:1158–1160. PubMed

Valentin-Vega YA, MacLean KH, Tait-Mulder J, Milasta S, Steeves M, Dorsey FC, Cleveland JL, Green DR, Kastan MB. Mitochondrial dysfunction in ataxia-telangiectasia. Blood. 2012;119:1490–5001. PubMed PMC

Veeriah S, Taylor BS, Meng S, Fang F, Yilmaz E, Vivanco I, Janakiraman M, Schultz N, Hanrahan AJ, Pao W, Ladanyi M, Sander C, Heguy A, Holland EC, Paty PB, Mischel PS, Liau L, Cloughesy TF, Mellinghoff IK, Solit DB, et al. Somatic mutations of the Parkinson’s disease-associated gene PARK2 in glioblastoma and other human malignancies. Nat Genet. 2010;42:77–82. PubMed PMC

Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA, Gocayne JD, Amanatides P, Ballew RM, Huson DH, Wortman JR, Zhang Q, Kodira CD, Zheng XH, Chen L, Skupski M, et al. The sequence of the human genome. Science. 2001;291:1304–1351. PubMed

Verstreken P, Ly CV, Venken KJT, Koh TW, Zhou Y, Bellen HJ. Synaptic mitochondria are critical for mobilization of reserve pool vesicles at drosophila neuromuscular junctions. Neuron. 2005;47:365–378. PubMed

Viana RJ, Nunes AF, Castro RE, Ramalho RM, Meyerson J, Fossati S, Ghiso J, Rostagno A, Rodrigues CM. Tauroursodeoxycholic acid prevents E22Q Alzheimer’s Abeta toxicity in human cerebral endothelial cells. Cell Mol Life Sci. 2009;66:1094–1104. PubMed PMC

Viana RJ, Nunes AF, Castro RE, Ramalho RM, Meyerson J, Fossati S, Ghiso J, Rostagno A, Rodrigues CM. Tauroursodeoxycholic acid prevents E22Q Alzheimer’s Abeta toxicity in human cerebral endothelial cells. Cell Mol Life Sci. 2009;66:1094–1104. PubMed PMC

Vicencio E, Beltrán S, Labrador L, Manque P, Nassif M, Woehlbier U. Implications of selective autophagy dysfunction for ALS pathology. Cells. 2020;9:381. PubMed PMC

Virbasius JV, Scarpulla RC. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc Natl Acad Sci U S A. 1994;91:1309–1313. PubMed PMC

Viscomi C, Bottani E, Zeviani M. Emerging concepts in the therapy of mitochondrial disease. Biochim Biophys Acta. 2015;1847(6-7):544–557. PubMed

Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL, Kim J. PINK1- dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci U S A. 2010;107:378–383. PubMed PMC

von Lewinski F, Keller BU. Ca2+, mitochondria and selective motoneuron vulnerability: implications for ALS. Trends Neurosci. 2005;28:494–500. PubMed

Wai T, Langer T. Mitochondrial dynamics and metabolic regulation. Trends Endocrinol Metab. 2016;27:105–117. PubMed

Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D. PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell. 2011;147:893–906. PubMed PMC

Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta. 2014;1842:1240–1247. PubMed PMC

Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, Zhu X. Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci. 2009;29:9090–9103. PubMed PMC

Wang Y, Liu N, Lu B. Mechanisms and roles of mitophagy in neurodegenerative diseases. CNS Neurosci Ther. 2019a;25:859–875. PubMed PMC

Wang Y, Xu E, Musich PR, Lin F. Mitochondrial dysfunction in neurodegenerative diseases and the potential countermeasure. CNS Neurosci Ther. 2019b;25:816–824. PubMed PMC

Wasiak S, Zunino R, McBride HM. Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death. J Cell Biol. 2007;177:439–450. PubMed PMC

Wei H, Liu L, Chen Q. Selective removal of mitochondria via mitophagy: distinct pathways for different mitochondrial stresses. Biochim Biophys Acta. 2015;1853:2784–2790. PubMed

Wei W, Keogh MJ, Wilson I, Coxhead J, Ryan S, Rollinson S, Griffin H, Kurzawa-Akanbi M, Santibanez-Koref M, Talbot K, Turner MR, McKenzie CA, Troakes C, Attems J, Smith C, Al Sarraj S, Morris CM, Ansorge O, Pickering-Brown S, Ironside JW, et al. Mitochondrial DNA point mutations and relative copy number in 1363 disease and control human brains. Acta Neuropathol Commun. 2017;5:13. PubMed PMC

Weydt P, Soyal SM, Gellera C, Didonato S, Weidinger C, Oberkofler H, Landwehrmeyer GB, Patsch W. The gene coding for PGC-1alpha modifies age at onset in Huntington’s Disease. Mol Neurodegener. 2009;4:3. PubMed PMC

World Health Organisation. Ageing and health. 2018. https://www.who.int/news-room/fact-sheets/detail/ageing-and-health .

Wiedau-Pazos M, Goto JJ, Rabizadeh S, Gralla EB, Roe JA, Lee MK, Valentine JS, Bredesen DE. Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis. Science. 1996;271:515–518. PubMed

Wilkins HM, Weidling IW, Ji Y, Swerdlow RH. Mitochondria-derived damage-associated molecular patterns in neurodegeneration. Front Immunol. 2017;8:508. PubMed PMC

Wojda U, Salinska E, Kuznicki J. Calcium ions in neuronal degeneration. IUBMB Life. 2008;60:575–590. PubMed

Wu W, Zhao D, Shah SZA, Zhang X, Lai M, Yang D, Wu X, Guan Z, Li J, Zhao H, Li W, Gao H, Zhou X, Qiao J, Yang L. OPA1 overexpression ameliorates mitochondrial cristae remodeling, mitochondrial dysfunction, and neuronal apoptosis in prion diseases. Cell Death Dis. 2019;10:710. PubMed PMC

Wu W, Wang X, Xiang Q, Meng X, Peng Y, Du N, Liu Z, Sun Q, Wang C, Liu X. Astaxanthin alleviates brain aging in rats by attenuating oxidative stress and increasing BDNF levels. Food Funct. 2014;5:158–166. PubMed

Xiang Z, Valenza M, Cui L, Leoni V, Jeong HK, Brilli E, Zhang J, Peng Q, Duan W, Reeves SA, Cattaneo E, Krainc D. Peroxisome-proliferator-activated receptor gamma coactivator 1 α contributes to dysmyelination in experimental models of Huntington’s disease. J Neurosci. 2011;31:9544–9553. PubMed PMC

Xun Z, Rivera-Sánchez S, Ayala-Peña S, Lim J, Budworth H, Skoda EM, Robbins PD, Niedernhofer LJ, Wipf P, McMurray CT. Targeting of XJB-5-131 to mitochondria suppresses oxidative DNA damage and motor decline in a mouse model of Huntington’s disease. Cell Rep. 2012;2:1137–1142. PubMed PMC

Yamada ES, Respondek G, Müssner S, de Andrade A, Höllerhage M, Depienne C, Rastetter A, Tarze A, Friguet B, Salama M, Champy P, Oertel WH, Höglinger GU. Annonacin, a natural lipophilic mitochondrial complex I inhibitor, increases phosphorylation of tau in the brain of FTDP-17 transgenic mice. Exp Neurol. 2014;253:113–125. PubMed

Yan X, Wang B, Hu Y, Wang S, Zhang X. Abnormal mitochondrial quality control in neurodegenerative diseases. Front Cell Neurosci. 2020;14:138. PubMed PMC

Yang Y, Herrup K. Loss of neuronal cell cycle control in Ataxia-telangiectasia: A unified disease mechanism. J Neurosci. 2005;25:2522–2529. PubMed PMC

Yang Y, Wu H, Kang X, Liang Y, Lan T, Li T, Tan T, Peng J, Zhang Q, An G, Liu Y, Yu Q, Ma Z, Lian Y, Soh BS, Chen Q, Liu P, Chen Y, Sun X, et al. Targeted elimination of mutant mitochondrial DNA in MELAS-iPSCs by mitoTALENs. Protein Cell. 2018;9:283–297. PubMed PMC

Ye X, Sun X, Starovoytov V, Cai Q. Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer’s disease patient brains. Hum Mol Genet. 2015;24:2938–2951. PubMed PMC

Yin F, Sancheti H, Patil I, Cadenas E. Energy metabolism and inflammation in brain aging and Alzheimer’s disease. Free Radic Biol Med. 2016;100:108–122. PubMed PMC

Yin J, Zhao F, Chojnacki JE, Fulp J, Klein WL, Zhang S, Zhu X. NLRP3 Inflammasome inhibitor ameliorates amyloid pathology in a mouse model of Alzheimer’s disease. Mol Neurobiol. 2018;55:1977–1987. PubMed PMC

Yogalingam G, Hwang S, Ferreira JC, Mochly-Rosen D. Glyceraldehyde3-phosphate dehydrogenase (GAPDH) phosphorylation by protein kinase Cδ (PKCδ) inhibits mitochondria elimination by lysosomal-like structures following ischemia and reoxygenation-induced injury. J Biol Chem. 2013;288:18947–18960. PubMed PMC

Youle RJ, van der Bliek AM. Mitochondrial fission, fusion and stress. Science. 2012;337:1062–1065. PubMed PMC

Yu JT, Chang RC, Tan L. Calcium dysregulation in Alzheimer’s disease: from mechanisms to therapeutic opportunities. Prog Neurobiol. 2009;89:240–255. PubMed

Yuan J, Amin P, Ofengeim D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci. 2019;20:19–33. PubMed PMC

Zenisek D, Matthews G. The role of mitochondria in presynaptic calcium handling at a ribbon synapse. Neuron. 2000;25:229–237. PubMed

Zhang S, Tang MB, Luo HY, Shi CH, Xu YM. Necroptosis in neurodegenerative diseases: A potential therapeutic target. Cell Death Dis 8. 2017:e2905. PubMed PMC

Zhang W, Gu GJ, Shen X, Zhang Q, Wang GM, Wang PJ. Neural stem cell transplantation enhances mitochondrial biogenesis in a transgenic mouse model of Alzheimer’s disease-like pathology. Neurobiol Aging. 2015;36:1282–1292. PubMed

Zhang ZY, Fan ZK, Cao Y, Jia ZQ, Li G, Zhi XD, Yu DS, Lv G. Acetyl-L-carnitine ameliorates mitochondrial damage and apoptosis following spinal cord injury in rats. Neurosci Lett. 2015;604:18–23. PubMed

Zhao Y, Zhao B. Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxid Med Cell Longev. 2013;2013:316523. PubMed PMC

Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, Eklund AC, Zhang-James Y, Kim PD, Hauser MA, Grünblatt E, Moran LB, Mandel SA, Riederer P, Miller RM, Federoff HJ, Wüllner U, Papapetropoulos S, Youdim MB, Cantuti-Castelvetri I, et al. PGC-1α, a potential therapeutic target for early intervention in Parkinson’s disease. Sci Transl Med. 2010;2:52ra73. PubMed PMC

Zhu T, Chen JL, Wang Q, Shao W, Qi B. Modulation of mitochondrial dynamics in neurodegenerative diseases: an insight into prion diseases. Front Aging Neurosci. 2018;10:336. PubMed PMC

Zhu X, Perry G, Smith MA, Wang X. Abnormal mitochondrial dynamics in the pathogenesis of Alzheimer’s disease. J Alzheimers Dis. 2013;33:S253–262. PubMed PMC

Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, Shulman GI. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A. 2002;99:15983–15987. PubMed PMC