Mitochondrial DNA (mtDNA) heteroplasmy is the dynamically determined co-expression of wild type (WT) inherited polymorphisms and collective time-dependent somatic mutations within individual mtDNA genomes. The temporal expression and distribution of cell-specific and tissue-specific mtDNA heteroplasmy in healthy individuals may be functionally associated with intracellular mitochondrial signaling pathways and nuclear DNA gene expression. The maintenance of endogenously regulated tissue-specific copy numbers of heteroplasmic mtDNA may represent a sensitive biomarker of homeostasis of mitochondrial dynamics, metabolic integrity, and immune competence. Myeloid cells, monocytes, macrophages, and antigen-presenting dendritic cells undergo programmed changes in mitochondrial metabolism according to innate and adaptive immunological processes. In the central nervous system (CNS), the polarization of activated microglial cells is dependent on strategically programmed changes in mitochondrial function. Therefore, variations in heteroplasmic mtDNA copy numbers may have functional consequences in metabolically competent mitochondria in innate and adaptive immune processes involving the CNS. Recently, altered mitochondrial function has been demonstrated in the progression of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Accordingly, our review is organized to present convergent lines of empirical evidence that potentially link expression of mtDNA heteroplasmy by functionally interactive CNS cell types to the extent and severity of acute and chronic post-COVID-19 neurological disorders.

Center for Cognitive and Molecular Neuroscience 1st Faculty of Medicine Charles University Prague Prague Czech Republic

Zobrazit více v PubMed

Al Amir Dache Z, Otandault A, Tanos R, Pastor B, Meddeb R, Sanchez C, Arena G, Lasorsa L, Bennett A, Grange T, El Messaoudi S, Mazard T, Prevostel C, Thierry AR (2020) Blood contains circulating cell-free respiratory competent mitochondria. FASEB J 34(3):3616–3630. 10.1096/fj.201901917RR PubMed

Allen JF (2015) Why chloroplasts and mitochondria retain their own genomes and genetic systems: Colocation for redox regulation of gene expression. PNAS 112:10231–10238. 10.1073/pnas.1500012112 PubMed PMC

Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG (1981) Sequence and organization of the human mitochondrial genome. Nature 290(5806):457–465. 10.1038/290457a0 PubMed

Angajala A, Lim S, Phillips JB, Kim JH, Yates C, You Z, Tan M (2018) Diverse roles of mitochondria in immune responses: novel insights into immuno-metabolism. Front Immunol 9:1605. 10.3389/fimmu.2018.01605 PubMed PMC

Aryaman J, Bowles C, Jones NS, Johnston IG (2019) Mitochondrial network state scales mtDNA genetic dynamics. Genetics 212(4):1429–1443. 10.1534/genetics.119.302423 PubMed PMC

Bedarf JR, Hildebrand F, Coelho LP, Sunagawa S, Bahram M, Goeser F, Bork P, Wullner U (2017) Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naive Parkinson’s disease patients. Genome Med 9(1):39. 10.1186/s13073-017-0428-y PubMed PMC

Bernier L, York EM, MacVicar BA (2020) Immunometabolism in the brain: how metabolism shapes microglial function. Trends Neurosci 43(11):854–869 PubMed

Bodea LG, Wang Y, Linnartz-Gerlach B, Kopatz J, Sinkkonen L, Musgrove R, Kaoma T, Muller A, Vallar L, Di Monte DA, Balling R, Neumann H (2014) Neurodegeneration by activation of the microglial complement-phagosome pathway. J Neurosci 34(25):8546–8556. 10.1523/JNEUROSCI.5002-13.2014 PubMed PMC

Braak H, Del Tredici K (2017) Neuropathological staging of brain pathology in sporadic Parkinson’s disease: separating the wheat from the chaff. J Parkinson’s Dis 7(S1):S73–S87. 10.3233/JPD-179001 PubMed PMC

Braak H, Rub U, Gai WP, Del Tredici K (2003) Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm (Vienna) 110(5):517–536. 10.1007/s00702-002-0808-2 PubMed

Burtscher J, Cappellano G, Omori A, Koshiba T, Millet GP (2020) Mitochondria: in the cross fire of SARS-CoV-2 and immunity. iScience. 10.1016/j.isci.2020.101631 PubMed PMC

Chandel NS (2014) Mitochondria as signaling organelles. BMC Biol 12:34. 10.1186/1741-7007-12-34 PubMed PMC

Crunfli F, Carregari VC, Veras F (2020) SARS-CoV-2 infects brain astrocytes of COVID-19 patients and impairs neuronal viability. 10.1101/2020.10.09.20207464

Davila AF, Zamorano P (2013) Mitochondria and the evolutionary roots of cancer. Phys Biol 10(2):026008. 10.1088/1478-3975/10/2/026008 PubMed

Deo P, Chow SH, Han ML, Speir M, Huang C, Schittenhelm RB, Dhital S, Emery J, Li J, Kile BT, Vince JE, Lawlor KE, Naderer T (2020) Mitochondrial dysfunction caused by outer membrane vesicles from Gram-negative bacteria activates intrinsic apoptosis and inflammation. Nat Microbiol 5(11):1418–1427. 10.1038/s41564-020-0773-2 PubMed

Devos D, Lebouvier T, Lardeux B, Biraud M, Rouaud T, Pouclet H, Coron E, Bruley des Varannes S, Naveilhan P, Nguyen JM, Neunlist M, Derkinderen P (2013) Colonic inflammation in Parkinson’s disease. Neurobiol Dis 50:42–48. 10.1016/j.nbd.2012.09.007 PubMed

Diaz Heijtz R, Wang S, Anuar F, Qian Y, Bjorkholm B, Samuelsson A, Hibberd ML, Forssberg H, Pettersson S (2011) Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA 108(7):3047–3052. 10.1073/pnas.1010529108 PubMed PMC

Dobbs RJ, Charlett A, Purkiss AG, Dobbs SM, Weller C, Peterson DW (1999) Association of circulating TNF-alpha and IL-6 with ageing and parkinsonism. Acta Neurol Scand 100(1):34–41. 10.1111/j.1600-0404.1999.tb00721.x PubMed

Dotan A, Muller S, Kanduc D, David P, Halpert G, Shoenfeld Y (2021) The SARS-CoV-2 as an instrumental trigger of autoimmunity. Autoimmun Rev. 10.1016/j.autrev.2021.102792 PubMed PMC

Esch T, Stefano GB (2002) Proinflammation: a common denominator or initiator of different pathophysiological disease processes. Med Sci Monitor 8(5):1–9 PubMed

Esch T, Stefano GB, Ptacek R, Kream RM (2020) Emerging roles of blood-borne intact and respiring mitochondria as bidirectional mediators of pro- and anti-inflammatory processes. Med Sci Monit. 10.12659/MSM.924337 PubMed PMC

Forsyth CB, Shannon KM, Kordower JH, Voigt RM, Shaikh M, Jaglin JA, Estes JD, Dodiya HB, Keshavarzian A (2011) Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS ONE 6(12):e28032. 10.1371/journal.pone.0028032 PubMed PMC

Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C, Ji X, Lo EH (2016) Transfer of mitochondria from astrocytes to neurons after stroke. Nature 535(7613):551–555 PubMed PMC

He Y, Wu J, Dressman DC, Iacobuzio-Donahue C, Markowitz SD, Velculescu VE, Diaz LA Jr, Kinzler KW, Vogelstein B, Papadopoulos N (2010) Heteroplasmic mitochondrial DNA mutations in normal and tumour cells. Nature 464(7288):610–614. 10.1038/nature08802 PubMed PMC

Hirose M, Kunstner A, Schilf P, Sunderhauf A, Rupp J, Johren O, Schwaninger M, Sina C, Baines JF, Ibrahim SM (2017) Mitochondrial gene polymorphism is associated with gut microbial communities in mice. Sci Rep 7(1):15293. 10.1038/s41598-017-15377-7 PubMed PMC

Hirose M, Kunstner A, Schilf P, Tietjen AK, Johren O, Huebbe P, Rimbach G, Rupp J, Schwaninger M, Busch H, Ibrahim SM (2019) A natural mtDNA polymorphism in complex III is a modifier of healthspan in mice. Int J Mol Sci 20(9):2359. 10.3390/ijms20092359 PubMed PMC

Hoitzing H, Gammage PA, Haute LV, Minczuk M, Johnston IG, Jones NS (2019) Energetic costs of cellular and therapeutic control of stochastic mitochondrial DNA populations. PLoS Comput Biol 15(6):e1007023. 10.1371/journal.pcbi.1007023 PubMed PMC

Jackson MV, Morrison TJ, Doherty DF, McAuley DF, Matthay MA, Kissenpfennig A, O’Kane CM, Krasnodembskaya AD (2016) Mitochondrial transfer via tunneling nanotubes (TNT) is an important mechanism by which mesenchymal stem cells enhance macrophage phagocytosis in the in vitro and in vivo models of ARDS. Stem Cells 34(8):2210–2223. 10.1002/stem.2372 PubMed PMC

Jacobi FK, Meyer J, Pusch CM, Wissinger B (2001) Quantitation of heteroplasmy in mitochondrial DNA mutations by primer extension using Vent(R)(exo-) DNA polymerase and RFLP analysis. Mutat Res 478(1–2):141–151. 10.1016/s0027-5107(01)00134-8 PubMed

Kitani T, Kami D, Matoba S, Gojo S (2014) Internalization of isolated functional mitochondria: involvement of macropinocytosis. J Cell Mol Med 18(8):1694–1703. 10.1111/jcmm.12316 PubMed PMC

Kosikowska U, Biernasiuk A, Korona-Glowniak I, Kiciak S, Tomasiewicz K, Malm A (2016) The association of chronic hepatitis c with respiratory microbiota disturbance on the basis of decreased Haemophilus spp. colonization. Med Sci Monit 22:625–632. 10.12659/msm.895544 PubMed PMC

Lebouvier T, Chaumette T, Paillusson S, Duyckaerts C, Bruley des VarannesNeunlistDerkinderen SMP (2009) The second brain and Parkinson’s disease. Eur J Neurosci 30(5):735–741. 10.1111/j.1460-9568.2009.06873.x PubMed

Lechuga-Vieco AV, Latorre-Pellicer A, Johnston IG, Prota G, Gileadi U, Justo-Mendez R, Acin-Perez R, Martinez-de-Mena R, Fernandez-Toro JM, Jimenez-Blasco D, Mora A, Nicolas-Avila JA, Santiago DJ, Priori SG, Bolanos JP, Sabio G, Criado LM, Ruiz-Cabello J, Cerundolo V, Jones NS, Enriquez JA (2020) Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics. Sci Adv 6(31):eaba5345. 10.1126/sciadv.aba5345 PubMed PMC

Lobet E, Letesson JJ, Arnould T (2015) Mitochondria: a target for bacteria. Biochem Pharmacol 94(3):173–185. 10.1016/j.bcp.2015.02.007 PubMed

Lynch MA (2020) Can the emerging field of immunometabolism provide insights into neuroinflammation? Prog Neurobiol 184:101719 PubMed

Main BS, Minter MR (2017) Microbial immuno-communication in neurodegenerative diseases. Front Neurosci 11:151. 10.3389/fnins.2017.00151 PubMed PMC

Malkki H (2017) Parkinson disease: could gut microbiota influence severity of Parkinson disease? Nat Rev Neurol 13(2):66–67. 10.1038/nrneurol.2016.195 PubMed

Manne BK, Denorme F, Middleton EA, Portier I, Rowley JW, Stubben C, Petrey AC, Tolley ND, Guo L, Cody M, Weyrich AS, Yost CC, Rondina MT, Campbell RA (2020) Platelet gene expression and function in patients with COVID-19. Blood 136(11):1317–1329. 10.1182/blood.2020007214 PubMed PMC

Matschke J, Lütgehetmann M, Hagel C, Sperhake JP, Schröder AS, Edler C, Mushumba H, Fitzek A, Allweiss L, Dandri M, Dottermusch M, Heinemann A, Pfefferle S, Schwabenland M, Sumner Magruder D, Bonn S, Prinz M, Gerloff C, Püschel K, Krasemann S, Aepfelbacher M, Glatzel M (2020) Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol 19(11):919–929 PubMed PMC

McCoy-Simandle K, Hanna SJ, Cox D (2016) Exosomes and nanotubes: control of immune cell communication. Int J Biochem Cell Biol 71:44–54. 10.1016/j.biocel.2015.12.006 PubMed PMC

McCully JD, Levitsky S, Del Nido PJ, Cowan DB (2016) Mitochondrial transplantation for therapeutic use. Clin Transl Med 5(1):16. 10.1186/s40169-016-0095-4 PubMed PMC

Mok BY, de Moraes MH, Zeng J, Bosch DE, Kotrys AV, Raguram A, Hsu F, Radey MC, Peterson SB, Mootha VK, Mougous JD, Liu DR (2020) A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing. Nature 583(7817):631–637. 10.1038/s41586-020-2477-4 PubMed PMC

Mulak A, Bonaz B (2015) Brain-gut-microbiota axis in Parkinson’s disease. World J Gastroenterol 21(37):10609–10620. 10.3748/wjg.v21.i37.10609 PubMed PMC

Müller-Nedebock AC, van der Westhuizen FH, Koks S, Bardien S (2021) Nuclear genes associated with mitochondrial DNA processes as contributors to Parkinson’s disease risk. Mov Disord. 10.1002/mds.28475 PubMed

Nagakawa K, Soyama A, Hidaka M, Adachi T, Ono S, Hara T, Takatsuki M, Eguchi S (2020) Elevated plasma levels of mitochondria-derived damage-associated molecular patterns during liver transplantation: predictors for postoperative multi-organ dysfunction syndrome. Tohoku J Exp Med 250(2):87–93. 10.1620/tjem.250.87 PubMed

Pacheu-Grau D, Gomez-Duran A, Iglesias E, Lopez-Gallardo E, Montoya J, Ruiz-Pesini E (2013) Mitochondrial antibiograms in personalized medicine. Hum Mol Genet 22(6):1132–1139. 10.1093/hmg/dds517 PubMed

Pollara J, Edwards RW, Lin L, Bendersky VA, Brennan TV (2018) Circulating mitochondria in deceased organ donors are associated with immune activation and early allograft dysfunction. JCI Insight 3(15):e121622. 10.1172/jci.insight.121622 PubMed PMC

Quiros PM, Mottis A, Auwerx J (2016) Mitonuclear communication in homeostasis and stress. Nat Rev Mol Cell Biol 17(4):213–226. 10.1038/nrm.2016.23 PubMed

Rietdijk CD, Perez-Pardo P, Garssen J, van Wezel RJ, Kraneveld AD (2017) Exploring Braak’s hypothesis of Parkinson’s disease. Front Neurol 8:37. 10.3389/fneur.2017.00037 PubMed PMC

Saint-Georges-Chaumet Y, Edeas M (2016) Microbiota-mitochondria inter-talk: consequence for microbiota-host interaction. Pathog Dis 74(1):ftv096. 10.1093/femspd/ftv096 PubMed

Scheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E, Haapaniemi E, Kaakkola S, Eerola-Rautio J, Pohja M, Kinnunen E, Murros K, Auvinen P (2015) Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord 30(3):350–358. 10.1002/mds.26069 PubMed

Schilf P, Künstner A, Olbrich M, Waschina S, Fuchs B, Galuska CE, Braun A, Neuschütz K, Seutter M, Bieber K, Hellberg L, Sina C, Laskay T, Rupp J, Ludwig RJ, Zillikens D, Busch H, Sadik CD, Hirose M, Ibrahim SM (2021) A mitochondrial polymorphism alters immune cell metabolism and protects mice from skin inflammation. Int J Mol Sci 22(3):1006. 10.3390/ijms22031006 PubMed PMC

Shenoy S (2020) Coronavirus (Covid-19) sepsis: revisiting mitochondrial dysfunction in pathogenesis, aging, inflammation, and mortality. Inflamm Res 69(11):1077–1085 PubMed PMC

Singh KK, Chaubey G, Chen JY, Suravajhala P (2020) Decoding SARS-CoV-2 hijacking of host mitochondria in COVID-19 pathogenesis. Am J Physiol Cell Physiol 319(2):C258–C267. 10.1152/ajpcell.00224.2020 PubMed PMC

Sonetti D, Ottaviani E, Bianchi F, Rodriquez M, Stefano ML, Scharrer B, Stefano GB (1994) Microglia in invertebrate ganglia. Proc Natl Acad Sci USA 91:9180–9184. 10.1073/pnas.91.19.9180 PubMed PMC

Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S, Lu P, Weizman OE, Liu F, Dai Y, Szigeti-Buck K, Yasumoto Y, Wang G, Castaldi C, Heltke J, Ng E, Wheeler J, Alfajaro MM, Levavasseur E, Fontes B, Ravindra NG, Van Dijk D, Mane S, Gunel M, Ring A, Kazmi SAJ, Zhang K, Wilen CB, Horvath TL, Plu I, Haik S, Thomas JL, Louvi A, Farhadian SF, Huttner A, Seilhean D, Renier N, Bilguvar K, Iwasaki A (2021) Neuroinvasion of SARS-CoV-2 in human and mouse brain J Exp Med. 218(3):e20202135 PubMed PMC

Song X, Hu W, Yu H, Wang H, Zhao Y, Korngold R, Zhao Y (2020) Existence of circulating mitochondria in human and animal peripheral blood. Int J Mol Sci 21(6):2122. 10.3390/ijms21062122 PubMed PMC

Stefano GB, Bilfinger TV, Fricchione GL (1994) The immune neuro-link and the macrophage: postcardiotomy delirium HIV-associated dementia and psychiatry. Prog Neurobiol 42(4):475–488. 10.1016/0301-0082(94)90048-5 PubMed

Stefano GB, Bjenning C, Wang F, Wang N, Kream RM (2017) Mitochondrial heteroplasmy. Adv Exp Med Biol 982:577–594. 10.1007/978-3-319-55330-6_30 PubMed

Stefano GB, Kream RM (2016) Mitochondrial DNA heteroplasmy in human health and disease. Biomed Rep 4:259–262. 10.3892/br.2016.590 PubMed PMC

Stefano GB, Mantione KJ, Capellan L, Casares FM, Challenger S, Ramin R, Samuel JM, Snyder C, Kream RM (2015) Morphine stimulates nitric oxide release in human mitochondria. J Bioenerg Biomembr 47(5):409–417. 10.1007/s10863-015-9626-8 PubMed

Stefano GB, Pilonis N, Ptacek R, Raboch J, Vnukova M, Kream RM (2018) Gut, microbiome, and brain regulatory axis: relevance to neurodegenerative and psychiatric disorders. Cell Mol Neurobiol 38:1197–1206. 10.1007/s10571-018-0589-2 PubMed PMC

Stefano ML, Kream RM, Stefano GB (2020) A novel vaccine employing non-replicating rabies virus expressing chimeric SARS-CoV-2 spike protein domains: functional inhibition of viral/nicotinic acetylcholine receptor complexes. Med Sci Monit. 10.12659/MSM.926016. PubMed PMC

Stefano GB, Ptacek R, Ptackova H, Martin A, Kream RM (2021) Selective neuronal mitochondrial targeting in SARS-CoV-2 infection affects cognitive processes to induce 'brain fog' and results in behavioral changes that favor viral survival. Med Sci Monit. 10.12659/MSM.930886. PubMed PMC

Taanman JW (1999) The mitochondrial genome: structure, transcription, translation and replication. Biochim Biophys Acta 1410(2):103–123. 10.1016/s0005-2728(98)00161-3 PubMed

Tatsuta T, Scharwey M, Langer T (2014) Mitochondrial lipid trafficking. Trends Cell Biol 24(1):44–52. 10.1016/j.tcb.2013.07.011 PubMed

Tiku V, Tan MW, Dikic I (2020) Mitochondrial functions in infection and immunity. Trends Cell Biol 30(4):263–275. 10.1016/j.tcb.2020.01.006 PubMed PMC

Tremlett H, Bauer KC, Appel-Cresswell S, Finlay BB, Waubant E (2017) The gut microbiome in human neurological disease: a review. Ann Neurol 81(3):369–382. 10.1002/ana.24901 PubMed

Verheijden S, De Schepper S, Boeckxstaens GE (2015) Neuron-macrophage crosstalk in the intestine: a “microglia” perspective. Front Cell Neurosci 9:403. 10.3389/fncel.2015.00403 PubMed PMC

Villaran RF, Espinosa-Oliva AM, Sarmiento M, De Pablos RM, Arguelles S, Delgado-Cortes MJ, Sobrino V, Van Rooijen N, Venero JL, Herrera AJ, Cano J, Machado A (2010) Ulcerative colitis exacerbates lipopolysaccharide-induced damage to the nigral dopaminergic system: potential risk factor in Parkinson`s disease. J Neurochem 114(6):1687–1700. 10.1111/j.1471-4159.2010.06879.x PubMed

Wang X, Gerdes HH (2015) Transfer of mitochondria via tunneling nanotubes rescues apoptotic PC12 cells. Cell Death Differ 22(7):1181–1191. 10.1038/cdd.2014.211 PubMed PMC

Wang F, Kream RM, Stefano GB (2020) Long-term respiratory and neurological sequelae of COVID-19. Med Sci Monit 26:e928996. 10.12659/MSM.928996 PubMed PMC

West AP, Shadel GS, Ghosh S (2011) Mitochondria in innate immune responses. Nat Rev Immunol 11(6):389–402. 10.1038/nri2975 PubMed PMC

Wu KE, Fazal FM, Parker KR, Zou J, Chang HY (2020) RNA-GPS predicts SARS-CoV-2 RNA residency to host mitochondria and nucleolus. Cell Syst 11(1):102–108e103. 10.1016/j.cels.2020.06.008 PubMed PMC

Yardeni T, Tanes CE, Bittinger K, Mattei LM, Schaefer PM, Singh LN, Wu GD, Murdock DG, Wallace DC (2019) Host mitochondria influence gut microbiome diversity: a role for ROS. Sci Signal 2(588):eaaw3159. 10.1126/scisignal.aaw3159 PubMed

Zhou L, Foster JA (2015) Psychobiotics and the gut-brain axis: in the pursuit of happiness. Neuropsychiatr Dis Treat 11:715–723. 10.2147/NDT.S61997 PubMed PMC

Zhu M, Barbas AS, Lin L, Scheuermann U, Bishawi M, Brennan TV (2018) Mitochondria released by apoptotic cell death initiate innate immune responses. Immunohorizons 2(11):384–397. 10.4049/immunohorizons.1800063 PubMed PMC

Zuo H, Wan Y (2019) Metabolic reprogramming in mitochondria of myeloid cells. Cells 9(1):5. 10.3390/cells9010005 PubMed PMC

Primordial Biochemicals Within Coacervate-Like Droplets and the Origins of Life

Potential Prion Involvement in Long COVID-19 Neuropathology, Including Behavior

Independent and sensory human mitochondrial functions reflecting symbiotic evolution

Biomedical Perspectives of Acute and Chronic Neurological and Neuropsychiatric Sequelae of COVID-19

HIV, HSV, SARS-CoV-2 and Ebola Share Long-Term Neuropsychiatric Sequelae

Viruses Broaden the Definition of Life by Genomic Incorporation of Artificial Intelligence and Machine Learning Processes

Dysfunctional mitochondrial processes contribute to energy perturbations in the brain and neuropsychiatric symptoms