The appearance of alpha-synuclein-positive inclusion bodies (Lewy bodies) and the loss of catecholaminergic neurons are the primary pathological hallmarks of Parkinson's disease (PD). However, the dysfunction of mitochondria has long been recognized as a key component in the progression of the disease. Dysfunctional mitochondria can in turn lead to dysregulation of calcium homeostasis and, especially in dopaminergic neurons, raised mean intracellular calcium concentration. As calcium binding to alpha-synuclein is one of the important triggers of alpha-synuclein aggregation, mitochondrial dysfunction will promote inclusion body formation and disease progression. Increased reactive oxygen species (ROS) resulting from inefficiencies in the electron transport chain also contribute to the formation of alpha-synuclein aggregates and neuronal loss. Recent studies have also highlighted defects in mitochondrial clearance that lead to the accumulation of depolarized mitochondria. Transaxonal and intracytoplasmic translocation of mitochondria along the microtubule cytoskeleton may also be affected in diseased neurons. Furthermore, nanotube-mediated intercellular transfer of mitochondria has recently been reported between different cell types and may have relevance to the spread of PD pathology between adjacent brain regions. In the current review, the contributions of both intracellular and intercellular mitochondrial dynamics to the etiology of PD will be discussed.

CNC Center for Neuroscience and Cell Biology University of Coimbra Cantanhede Portugal

Institute of Biotechnology Czech Academy of Sciences Prague West Czechia

School of Medical Science Griffith University Southport QLD Australia

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Abounit S., Bousset L., Loria F., Zhu S., de Chaumont F., Pieri L., et al. (2016). Tunneling nanotubes spread fibrillar α-synuclein by intercellular trafficking of lysosomes. PubMed DOI PMC

Ahmad T., Mukherjee S., Pattnaik B., Kumar M., Singh S., Kumar M., et al. (2014). Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy. PubMed DOI PMC

Barsoum M. J., Yuan H., Gerencser A. A., Liot G., Kushnareva Y., Graber S., et al. (2006). Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. PubMed DOI PMC

Bartels T., Choi J., Selkoe D. (2011). α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. PubMed DOI PMC

Bayliss J., Lemus M., Santos V., Deo M., Davies J., Kemp B., et al. (2016). Metformin prevents nigrostriatal dopamine degeneration independent of AMPK activation in dopamine neurons. PubMed DOI PMC

Berridge M., Dong L., Neuzil J. (2015). Mitochondrial DNA in tumor initiation, progression, and metastasis: role of horizontal mtDNA transfer. PubMed DOI

Berridge M., McConnell M., Grasso C., Bajzikova M., Kovarova J., Neuzil J. (2016). Horizontal transfer of mitochondria between mammalian cells: beyond co-culture approaches. PubMed DOI

Burre J., Sharma M., Tsetsenis T., Buchman V., Etherton M., Sudhof T. (2010). α-Synuclein promotes SNARE-complex assembly in vivo and in vitro. PubMed DOI PMC

Burte F., Carelli V., Chinnery P. F., Yu-Wai-Man P. (2015). Disturbed mitochondrial dynamics and neurodegenerative disorders. PubMed DOI

Cai Q., Gerwin C., Sheng Z. H. (2005). Syntabulin-mediated anterograde transport of mitochondria along neuronal processes. PubMed DOI PMC

Celardo I., Martins L. M., Gandhi S. (2014). Unravelling mitochondrial pathways to Parkinson’s disease. PubMed DOI PMC

Chan D. C. (2012). Fusion and fission: interlinked processes critical for mitochondrial health. PubMed DOI

Chen C., Turnbull D. M., Reeve A. K. (2019). Mitochondrial dysfunction in Parkinson’s disease-cause or consequence? PubMed PMC

Chen Y., Sheng Z. H. (2013). Kinesin-1-syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport. PubMed DOI PMC

Chu C. T. (2018). Multiple pathways for mitophagy: a neurodegenerative conundrum for Parkinson’ disease. PubMed DOI PMC

Chu C. T., Ji J., Dagda R. K., Jiang J. F., Tyurina Y. Y., Kapralov A. A., et al. (2013). Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. PubMed DOI PMC

Chu Y., Morfini G., Langhamer L., He Y., Brady S., Kordower J. (2012). Alterations in axonal transport motor proteins in sporadic and experimental Parkinson’s disease. PubMed DOI PMC

Clark I. E., Dodson M. W., Jiang C., Cao J. H., Huh J. R., Seol J. H., et al. (2006). Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. PubMed DOI

Cole N. B., Dieuliis D., Leo P., Mitchell D. C., Nussbaum R. L. (2008). Mitochondrial translocation of alpha-synuclein is promoted by intracellular acidification. PubMed DOI PMC

Davis C., Kim K., Bushong E., Mills E., Boassa D., Shih T., et al. (2014). Transcellular degradation of axonal mitochondria. PubMed DOI PMC

Davis C., Xi Z. (2015). Horizontal gene transfer in parasitic plants. PubMed DOI

Dawson T. M., Dawson V. L. (2010). The role of parkin in familial and sporadic Parkinson’s disease. PubMed DOI PMC

Devi L., Raghavendran V., Prabhu B. M., Avadhani N. G., Anandatheerthavarada H. K. (2008). Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. PubMed DOI PMC

Di Maio R., Barrett P., Hoffman E., Barrett C., Zharikov A., Borah A., et al. (2016). α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease. PubMed DOI PMC

Dieriks B., Park T., Fourie C., Faull R., Dragunow M., Curtis M. (2017). α-synuclein transfer through tunneling nanotubes occurs in SH-SY5Y cells and primary brain pericytes from Parkinson’s disease patients. PubMed PMC

Dong L., Kovarova J., Bajzikova M., Coelho A., Boukalova S., Rohlena J., et al. (2018). Horizontal transfer of mitochondria and dihydroorotate dehydrogenase function in respiration recovery of mtDNA deficient cancer cells.

Dorban G., Defaweux V., Heinen E., Antoine N. (2010). Spreading of prions from the immune to the peripheral nervous system: a potential implication of dendritic cells. PubMed DOI

Dorn G. W., II, Kitsis R. N. (2015). The mitochondrial dynamism-mitophagy-cell death interactome: multiple roles performed by members of a mitochondrial molecular ensemble. PubMed DOI PMC

El-Agnaf O., Salem S., Paleologou K., Curran M., Gibson M., Court J., et al. (2006). Detection of oligomeric forms of α-synuclein protein in human plasma as a potential biomarker for Parkinson’s disease. PubMed DOI

Fu J., Yu H., Chiu S., Mirando A., Maruyama E., Cheng J., et al. (2014). Disruption of SUMO-Specific Protease 2 induces mitochondria mediated neurodegeneration. PubMed DOI PMC

Fujiwara H., Hasegawa M., Dohmae N., Kawashima A., Masliah E., Goldberg M., et al. (2002). α-Synuclein is phosphorylated in synucleinopathy lesions. PubMed DOI

Gillardon F. (2009). Leucine-rich repeat kinase 2 phosphorylates brain tubulin-beta isoforms and modulates microtubule stability–a point of convergence in parkinsonian neurodegeneration? PubMed DOI

Godena V. K., Brookes-Hocking N., Moller A., Shaw G., Oswald M., Sancho R. M., et al. (2014). Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations. PubMed DOI PMC

Gousset K., Schiff E., Langevin C., Marijanovic Z., Caputo A., Browman D., et al. (2009). Prions hijack tunnelling nanotubes for intercellular spread. PubMed DOI

Grassi D., Howard S., Zhou M., Diaz-Perez N., Urban N., Guerrero-Given D., et al. (2018). Identification of a highly neurotoxic α-synuclein species inducing mitochondrial damage and mitophagy in Parkinson’s disease. PubMed PMC

Grossmann D., Berenguer-Escuder C., Bellet M. E., Scheibner D., Bohler J., Massart F. (2019). Mutations in RHOT1 disrupt ER-mitochondria contact sites interfering with calcium homeostasis and mitochondrial dynamics in Parkinson’s disease. PubMed DOI PMC

Guo C., Hildick K. L., Luo J., Dearden L., Wilkinson K. A., Henley J. M. (2013). SENP3-mediated deSUMOylation of dynamin-related protein 1 promotes cell death following ischaemia. PubMed DOI PMC

Guo C., Wilkinson K. A., Evans A. J., Rubin P. P., Henley J. M. (2017). SENP3-mediated deSUMOylation of Drp1 facilitates interaction with Mff to promote cell death. PubMed DOI PMC

Hase K., Kimura S., Takatsu H., Ohmae M., Kawano S., Kitamura H., et al. (2009). M-Sec promotes membrane nanotube formation by interacting with Ral and the exocyst complex. PubMed DOI

Henley J. M., Carmichael R. E., Wilkinson K. A. (2018). Extranuclear SUMOylation in Neurons. PubMed DOI

Hirokawa N., Niwa S., Tanaka Y. (2010). Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease. PubMed DOI

Islam M. N., Das S. R., Emin M. T., Wei M., Sun L., Westphalen K., et al. (2012). Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. PubMed DOI PMC

Ismaiel A. A., Espinosa-Oliva A. M., Santiago M., García-Quintanilla A., Oliva-Martín M. J., Herrera A. J., et al. (2016). Metformin, besides exhibiting strong PubMed DOI

Jayaprakash A. D., Benson E. K., Gone S., Liang R., Shim J., Lambertini L., et al. (2015). Stable heteroplasmy at the single-cell level is facilitated by intercellular exchange of mtDNA. PubMed DOI PMC

Kamp F., Exner N., Lutz A. K., Wender N., Hegermann J., Brunner B., et al. (2010). Inhibition of mitochondrial fusion by alpha-synuclein is rescued by PINK1. Parkin and DJ-1. PubMed DOI PMC

Keeling P., Palmer J. (2008). Horizontal gene transfer in eukaryotic evolution. PubMed DOI

Kimura S., Hase K., Ohno H. (2012). Tunneling nanotubes: Emerging view of their molecular components and formation mechanisms. PubMed DOI

Korobova F., Ramabhadran V., Higgs H. N. (2013). An actin-dependent step in mitochondrial fission mediated by the ER-associated formin INF2. PubMed DOI PMC

Kumar A., Tamjar J., Waddell A., Woodroof H., Raimi O., Shaw A., et al. (2017). Structure of PINK1 and mechanisms of Parkinson’ disease-associated mutations. PubMed PMC

Langley M., Ghosh A., Charli A., Sarkar S., Ay M., Luo J., et al. (2017). Mito-apocynin prevents mitochondrial dysfunction, microglial activation, oxidative damage, and progressive neurodegeneration in mitopark transgenic mice. PubMed DOI PMC

Lee K. S., Huh S., Lee S., Wu Z., Kim A. K., Kang H. Y., et al. (2018). Altered ER-mitochondria contact impacts mitochondria calcium homeostasis and contributes to neurodegeneration in vivo in disease models. PubMed DOI PMC

Lin M., Cantuti-Castelvetri I., Zheng K., Jackson K., Tan Y., Arzberger T., et al. (2012). Somatic mitochondrial DNA mutations in early parkinson and incidental lewy body disease. PubMed DOI PMC

Lin M. Y., Sheng Z. H. (2015). Regulation of mitochondrial transport in neurons. PubMed DOI PMC

Liu S., Sawada T., Lee S., Yu W., Silverio G., Alapatt P., et al. (2012). Parkinson’s disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria. PubMed DOI PMC

Lonskaya I., Hebron M., Algarzae N., Desforges N., Moussa C. (2013). Decreased parkin solubility is associated with impairment of autophagy in the nigrostriatum of sporadic Parkinson’s disease. PubMed DOI PMC

Lu M., Su C., Qiao C., Bian Y., Ding J., Hu G. (2016). Metformin prevents dopaminergic neuron death in MPTP/P-induced mouse model of parkinson’s disease via autophagy and mitochondrial ROS clearance. PubMed PMC

MacAskill A., Kittler J. (2010). Control of mitochondrial transport and localization in neurons. PubMed DOI

MacAskill A., Rinholm J., Twelvetrees A., Arancibia-Carcamo I., Muir J., Fransson A., et al. (2009). Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses. PubMed DOI PMC

Martinez-Vicente M. (2017). Neuronal mitophagy in neurodegenerative diseases. PubMed DOI PMC

Mata I. F., Lockhart P. J., Farrer M. J. (2004). Parkin genetics: one model for Parkinson’s disease. PubMed

McCann H., Stevens C., Cartwright H., Halliday G. (2014). α-Synucleinopathy phenotypes. PubMed

McLeary F. A., Rcom-H’cheo-Gauthier A. N., Goulding M., Radford R. A. W., Okita Y., Faller P., et al. (2019). Switching on Endogenous metal binding proteins in Parkinson’s Disease. PubMed DOI PMC

Meissner C., Lorenz H., Hehn B., Lemberg M. K. (2015). Intramembrane protease PARL defines a negative regulator of PINK1- and PARK2/Parkin-dependent mitophagy. PubMed DOI PMC

Melkov A., Abdu U. (2018). Regulation of long-distance transport of mitochondria along microtubules. PubMed DOI PMC

Melo T. Q., Van Zomeren K. C., Ferrari M. F., Boddeke H. W., Copray J. C. (2017). Impairment of mitochondria dynamics by human A53T alpha-synuclein and rescue by NAP (davunetide) in a cell model for Parkinson’s disease. PubMed DOI PMC

Morfini G., Pigino G., Opalach K., Serulle Y., Moreira J. E., Sugimori M., et al. (2007). 1-Methyl-4-phenylpyridinium affects fast axonal transport by activation of caspase and protein kinase C. PubMed DOI PMC

Nemani N., Carvalho E., Tomar D., Dong Z., Ketschek A., Breves S. L. (2018). MIRO-1 determines mitochondrial shape transition upon GPCR activation and Ca2+ Stress. PubMed DOI PMC

O’Donnell K. C., Lulla A., Stahl M. C., Wheat N. D., Bronstein J. M., Sagasti A. (2014). Axon degeneration and PGC-1alpha-mediated protection in a zebrafish model of alpha-synuclein toxicity. PubMed DOI PMC

Pagliuso A., Cossart P., Stavru F. (2018). The ever-growing complexity of the mitochondrial fission machinery. PubMed DOI PMC

Patil S., Jain P., Ghumatkar P., Tambe R., Sathaye S. (2014). Neuroprotective effect of metformin in MPTP-induced Parkinson’s disease in mice. PubMed DOI

Perfeito R., Cunha-Oliveira T., Rego A. C. (2013). Reprint of: revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease-resemblance to the effect of amphetamine drugs of abuse. PubMed DOI

Pozo Devoto V. M., Falzone T. L. (2017). Mitochondrial dynamics in Parkinson’s disease: a role for alpha-synuclein? PubMed DOI PMC

Prots I., Grosch J., Brazdis R., Simmnacher K., Veber V., Havlicek S., et al. (2018). α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies. PubMed DOI PMC

Prots I., Veber V., Brey S., Campioni S., Buder K., Riek R., et al. (2013). Alpha-synuclein oligomers impair neuronal microtubule-kinesin interplay. PubMed DOI PMC

Prusiner S., Woerman A., Mordes D., Watts J., Rampersaud R., Berry D., et al. (2015). Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism. PubMed PMC

Rcom-H’cheo-Gauthier A. N., Meedeniya A. C., Pountney D. L. (2017). Calcipotriol inhibits α-synuclein aggregation in SH-SY5Y neuroblastoma cells by a Calbindin-D28k-dependent mechanism. PubMed DOI

Rcom-H’cheo-Gauthier A. N., Osborne S., Meedeniya A., Pountney D. (2016). Calcium: alpha-synuclein interactions in alpha-synucleinopathies. PubMed DOI PMC

Reeve A., Ludtmann M., Angelova P., Simcox E., Horrocks M., Klenerman D., et al. (2015). Aggregated α-synuclein and complex I deficiency: exploration of their relationship in differentiated neurons. PubMed DOI PMC

Reynolds A., Glanzer J., Kadiu I., Ricardo-Dukelow M., Chaudhuri A., Ciborowski P., et al. (2008). Nitrated alpha-synuclein-activated microglial profiling for Parkinson’s disease. PubMed DOI

Rodolfo C., Campello S., Cecconi F. (2018). Mitophagy in neurodegenerative diseases. PubMed DOI

Rogers R., Bhatacharya J. (2013). When cells become organelle donors. PubMed DOI

Rostami J., Holmqvist S., Lindström V., Sigvardson J., Westermark G., Ingelsson M., et al. (2017). Human astrocytes transfer aggregated alpha-synuclein via tunneling nanotubes. PubMed DOI PMC

Rustom A. (2016). The missing link: does tunnelling nanotube-based supercellularity provide a new understanding of chronic and lifestyle diseases? PubMed DOI PMC

Rustom A., Saffrich R., Markovic I., Walther P., Gerdes H. H. (2004). Nanotubular highways for intercellular organelle transport. PubMed DOI

Saotome M., Safiulina D., Szabadkai G., Das S., Fransson A., Aspenstrom P., et al. (2008). Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase. PubMed DOI PMC

Schiller C., Diakopoulos K., Rohwedder I., Kremmer E., von Toerne C., Ueffing M., et al. (2013). LST1 promotes the assembly of a molecular machinery responsible for tunneling nanotube formation. PubMed DOI

Shaltouki A., Hsieh C., Kim M., Wang X. (2018). Alpha-synuclein delays mitophagy and targeting Miro rescues neuron loss in Parkinson’s models. PubMed DOI PMC

Sheng Z. H. (2017). The Interplay of axonal energy homeostasis and mitochondrial trafficking and anchoring. PubMed DOI PMC

Shirihai O. S., Song M., Dorn G. W., II (2015). How mitochondrial dynamism orchestrates mitophagy. PubMed DOI PMC

Shlevkov E., Kramer T., Schapansky J., LaVoie M., Schwarz T. (2016). Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility. PubMed PMC

Shults C. W. (2006). Lewy bodies. PubMed PMC

Sinha P., Islam M., Bhattacharya S., Bhattacharya J. (2016). Intercellular mitochondrial transfer: bioenergetic crosstalk between cells. PubMed DOI PMC

Spees J., Olson S., Whitney M., Prockop D. (2006). Mitochondrial transfer between cells can rescue aerobic respiration. PubMed DOI PMC

Steiner J., Quansah E., Brundin P. (2018). The concept of alpha-synuclein as a prion-like protein: ten years after. PubMed DOI PMC

Sulzer D., Edwards R. H. (2019). The physiological role of α-synuclein and its relationship to Parkinson’s Disease. PubMed DOI PMC

Suzuki S., Akamatsu W., Kisa F., Sone T., Ishikawa K. I., Kuzumaki N., et al. (2017). Efficient induction of dopaminergic neuron differentiation from induced pluripotent stem cells reveals impaired mitophagy in PARK2 neurons. PubMed DOI

Tan A., Baty J., Dong L., Bezawork-Geleta A., Endaya B., Goodwin J., et al. (2015). Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. PubMed DOI

Tas R. P., Kapitein L. C. (2018). Exploring cytoskeletal diversity in neurons. PubMed DOI

Thakur P., Chiu W. H., Roeper J., Goldberg J. A. (2019). α-Synuclein 2.0 — Moving towards Cell Type Specific Pathophysiology. PubMed DOI

Theillet F., Binolfi A., Bekei B., Martorana A., Rose H., Stuiver M., et al. (2016). Structural disorder of monomeric α-synuclein persists in mammalian cells. PubMed DOI

Thomas K. J., Mccoy M. K., Blackinton J., Beilina A., Van Der Brug M., Sandebring A., et al. (2011). DJ-1 acts in parallel to the PINK1/parkin pathway to control mitochondrial function and autophagy. PubMed DOI PMC

Tilokani L., Nagashima S., Paupe V., Prudent J. (2018). Mitochondrial dynamics: overview of molecular mechanisms. PubMed DOI PMC

Valdinocci D., Radford R., Siow S., Chung R., Pountney D. (2017). Potential modes of intercellular α-synuclein transmission. PubMed DOI PMC

Valente E. M., Bentivoglio A. R., Dixon P. H., Ferraris A., Ialongo T., Frontali M., et al. (2001). Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36. PubMed DOI PMC

Vijayakumaran S., Pountney D. L. (2018). SUMOylation, aging and autophagy in neurodegeneration. PubMed DOI

Vijayakumaran S., Wong M. B., Antony H., Pountney D. L. (2015). Direct and/or indirect roles for SUMO in modulating alpha-synuclein toxicity. PubMed DOI PMC

Wang X., Becker K., Levine N., Zhang M., Lieberman A., Moore D., et al. (2019). Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration. PubMed DOI PMC

Wang X., Gerdes H. H. (2015). Transfer of mitochondria via tunneling nanotubes rescues apoptotic PC12 cells. PubMed DOI PMC

Wang X., Schwarz T. (2009). The mechanism of Ca2+-dependent regulation of kinesin-mediated mitochondrial motility. PubMed DOI PMC

Wang X., Su B., Liu W., He X., Gao Y., Castellani R. J., et al. (2011a). DLP1-dependent mitochondrial fragmentation mediates 1-methyl-4-phenylpyridinium toxicity in neurons: implications for Parkinson’s disease. PubMed DOI PMC

Wang X., Winter D., Ashrafi G., Schlehe J., Wong Y., Selkoe D., et al. (2011b). PINK1 and parkin target miro for phosphorylation and degradation to arrest mitochondrial motility. PubMed DOI PMC

Winslow A. R., Chen C. W., Corrochano S., Acevedo-Arozena A., Gordon D. E., Peden A. A., et al. (2010). Alpha-Synuclein impairs macroautophagy: implications for Parkinson’s disease. PubMed DOI PMC

Xi Y., Feng D., Tao K., Wang R., Shi Y., Qin H., et al. (2018). MitoQ protects dopaminergic neurons in a 6-OHDA induced PD model by enhancing Mfn2-dependent mitochondrial fusion via activation of PGC-1α. PubMed DOI

Xie W., Chung K. K. (2012). Alpha-synuclein impairs normal dynamics of mitochondria in cell and animal models of Parkinson’s disease. PubMed DOI

Yoshii S. R., Mizushima N. (2015). Autophagy machinery in the context of mammalian mitophagy. PubMed DOI

Zala D., Hinckelmann M. V., Yu H., Lyra Da Cunha M. M., Liot G., Cordelieres F. P., et al. (2013). Vesicular glycolysis provides on-board energy for fast axonal transport. PubMed DOI

Zilocchi M., Finzi G., Lualdi M., Sessa F., Fasano M., Alberio T. (2018). Mitochondrial alterations in Parkinson’s disease human samples and cellular models. PubMed DOI

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