Involvement of Mitochondria in Parkinson’s Disease
<p>Extracellular mitochondria in PD. (a) In rotenone-induced mitochondrial impairment and parkin-deficient models, damaged mitochondria were extruded from cells in free form or membrane-surrounded vesicles. (b) In a 6-OHDA rodent model of PD, dopaminergic neurons showed accumulation of damaged mitochondria in spheroid structures. These spheroids were penetrated by astrocytic processes, and the mitochondria were transferred to astrocytes and degraded through mitophagy. (c) Neurons can release damaged mitochondria to be internalized by adjacent astrocytes for clearance. On the contrary, astrocytes can release functional mitochondria that enter neurons. (d) In a mouse model of PD with dementia, oxidized mtDNA could be observed being released outside the neurons. Injection of damaged mtDNA into the wild-type mouse brain triggers PD-like pathology including dopaminergic neuronal loss, pSyn accumulation and astrogliosis in the lesioned site. Damaged mtDNA also spread neurodegeneration to distant brain regions. The figure was created with BioRender.com, accessed on 28 November 2023.</p> "> Figure 2
<p>Mitochondrial transfer in PD. Mitochondrial treatment via intravenous administration in experimental MPTP mouse model and intranasal delivery and injection into medial forebrain bundle in 6-OHDA rat model resulted in mitochondrial function recovery, improved neuronal survival and better behavioral outcomes. The figure was created with BioRender.com, accessed on 30 November 2023.</p> ">
Abstract
:1. Introduction
2. Origin of the Link of Mitochondria to PD
3. Genes Particularly Associated with Mitochondrial Dysfunction in PD
3.1. Parkin
3.2. PINK1
3.3. Fbxo7
3.4. Alpha Synuclein
3.5. DJ-1
3.6. CHCHD2
3.7. VPS13C
4. Extracellular Mitochondria in Neurological Diseases
5. Mitochondrial Transfer in PD
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Perier, C.; Vila, M. Mitochondrial Biology and Parkinson’s Disease. Cold Spring Harb. Perspect. Med. 2012, 2, a009332. [Google Scholar] [CrossRef] [PubMed]
- Camandola, S.; Mattson, M.P. Brain Metabolism in Health, Aging, and Neurodegeneration. EMBO J. 2017, 36, 1474–1492. [Google Scholar] [CrossRef] [PubMed]
- Schapira, A.H.V.; Cooper, J.M.; Dexter, D.; Clark, J.B.; Jenner, P.; Marsden, C.D. Mitochondrial Complex I Deficiency in Parkinson’s Disease. J. Neurochem. 1990, 54, 823–827. [Google Scholar] [CrossRef]
- Keeney, P.M.; Xie, J.; Capaldi, R.A.; Bennett, J.P. Parkinson’s Disease Brain Mitochondrial Complex I Has Oxidatively Damaged Subunits and Is Functionally Impaired and Misassembled. J. Neurosci. 2006, 26, 5256–5264. [Google Scholar] [CrossRef] [PubMed]
- Bender, A.; Krishnan, K.J.; Morris, C.M.; Taylor, G.A.; Reeve, A.K.; Perry, R.H.; Jaros, E.; Hersheson, J.S.; Betts, J.; Klopstock, T.; et al. High Levels of Mitochondrial DNA Deletions in Substantia Nigra Neurons in Aging and Parkinson Disease. Nat. Genet. 2006, 38, 515–517. [Google Scholar] [CrossRef] [PubMed]
- Kraytsberg, Y.; Kudryavtseva, E.; McKee, A.C.; Geula, C.; Kowall, N.W.; Khrapko, K. Mitochondrial DNA Deletions Are Abundant and Cause Functional Impairment in Aged Human Substantia Nigra Neurons. Nat. Genet. 2006, 38, 518–520. [Google Scholar] [CrossRef] [PubMed]
- Nido, G.S.; Dölle, C.; Flønes, I.; Tuppen, H.A.; Alves, G.; Tysnes, O.B.; Haugarvoll, K.; Tzoulis, C. Ultradeep Mapping of Neuronal Mitochondrial Deletions in Parkinson’s Disease. Neurobiol. Aging 2018, 63, 120–127. [Google Scholar] [CrossRef] [PubMed]
- Tresse, E.; Marturia-Navarro, J.; Qi, W.; Sew, G.; Cisquella-Serra, M.; Jaberi, E.; Riera-Ponsati, L.; Fauerby, N.; Hu, E.; Kretz, O.; et al. Mitochondrial DNA Damage Triggers Spread of Parkinson’s Disease-like Pathology. Mol. Psychiatry 2023, 1–13. [Google Scholar] [CrossRef]
- Reeve, A.; Meagher, M.; Lax, N.; Simcox, E.; Hepplewhite, P.; Jaros, E.; Turnbull, D. The Impact of Pathogenic Mitochondrial DNA Mutations on Substantia Nigra Neurons. J. Neurosci. 2013, 33, 10790. [Google Scholar] [CrossRef]
- Kitada, T.; Asakawa, S.; Hattori, N.; Matsumine, H.; Yamamura, Y.; Minoshima, S.; Yokochi, M.; Mizuno, Y.; Shimizu, N. Mutations in the Parkin Gene Cause Autosomal Recessive Juvenile Parkinsonism. Nature 1998, 392, 605–608. [Google Scholar] [CrossRef]
- Valente, E.M.; Abou-Sleiman, P.M.; Caputo, V.; Muqit, M.M.K.; Harvey, K.; Gispert, S.; Ali, Z.; Del Turco, D.; Bentivoglio, A.R.; Healy, D.G.; et al. Hereditary Early-Onset Parkinson’s Disease Caused by Mutations in PINK1. Science 2004, 304, 1158–1160. [Google Scholar] [CrossRef]
- Bonifati, V.; Rizzu, P.; Van Baren, M.J.; Schaap, O.; Breedveld, G.J.; Krieger, E.; Dekker, M.C.J.; Squitieri, F.; Ibanez, P.; Joosse, M.; et al. Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism. Science 2003, 299, 256–259. [Google Scholar] [CrossRef] [PubMed]
- Karimi-Moghadam, A.; Charsouei, S.; Bell, B.; Jabalameli, M.R. Parkinson Disease from Mendelian Forms to Genetic Susceptibility: New Molecular Insights into the Neurodegeneration Process. Cell. Mol. Neurobiol. 2018, 38, 1153. [Google Scholar] [CrossRef] [PubMed]
- Choong, C.J.; Okuno, T.; Ikenaka, K.; Baba, K.; Hayakawa, H.; Koike, M.; Yokota, M.; Doi, J.; Kakuda, K.; Takeuchi, T.; et al. Alternative Mitochondrial Quality Control Mediated by Extracellular Release. Autophagy 2021, 17, 2962–2974. [Google Scholar] [CrossRef] [PubMed]
- Hayakawa, K.; Esposito, E.; Wang, X.; Terasaki, Y.; Liu, Y.; Xing, C.; Ji, X.; Lo, E.H. Transfer of Mitochondria from Astrocytes to Neurons after Stroke. Nature 2016, 535, 551–555. [Google Scholar] [CrossRef]
- Chou, S.H.Y.; Lan, J.; Esposito, E.; Ning, M.M.; Balaj, L.; Ji, X.; Lo, E.H.; Hayakawa, K. Extracellular Mitochondria in Cerebrospinal Fluid and Neurological Recovery after Subarachnoid Hemorrhage. Stroke 2017, 48, 2231. [Google Scholar] [CrossRef] [PubMed]
- Pyle, A.; Brennan, R.; Kurzawa-Akanbi, M.; Yarnall, A.; Thouin, A.; Mollenhauer, B.; Burn, D.; Chinnery, P.F.; Hudson, G. Reduced Cerebrospinal Fluid Mitochondrial DNA Is a Biomarker for Early-Stage Parkinson’s Disease. Ann. Neurol. 2015, 78, 1000–1004. [Google Scholar] [CrossRef] [PubMed]
- Jain, R.; Begum, N.; Tryphena, K.P.; Singh, S.B.; Srivastava, S.; Rai, S.N.; Vamanu, E.; Khatri, D.K. Inter and Intracellular Mitochondrial Transfer: Future of Mitochondrial Transplant Therapy in Parkinson’s Disease. Biomed. Pharmacother. 2023, 159, 114268. [Google Scholar] [CrossRef]
- Spees, J.L.; Olson, S.D.; Whitney, M.J.; Prockop, D.J. Mitochondrial Transfer between Cells Can Rescue Aerobic Respiration. Proc. Natl. Acad. Sci. USA 2006, 103, 1283–1288. [Google Scholar] [CrossRef]
- Islam, M.N.; Das, S.R.; Emin, M.T.; Wei, M.; Sun, L.; Westphalen, K.; Rowlands, D.J.; Quadri, S.K.; Bhattacharya, S.; Bhattacharya, J. Mitochondrial Transfer from Bone-Marrow–Derived Stromal Cells to Pulmonary Alveoli Protects against Acute Lung Injury. Nat. Med. 2012, 18, 759–765. [Google Scholar] [CrossRef]
- William Langston, J.; Ballard, P.; Tetrud, J.W.; Irwin, I. Chronic Parkinsonism in Humans Due to a Product of Meperidine-Analog Synthesis. Science 1983, 219, 979–980. [Google Scholar] [CrossRef] [PubMed]
- Nicklas, W.J.; Vyas, I.; Heikkila, R.E. Inhibition of NADH-Linked Oxidation in Brain Mitochondria by 1-Methyl-4-Phenyl-Pyridine, a Metabolite of the Neurotoxin, 1-Methyl-4-Phenyl-1,2,5,6-Tetrahydropyridine. Life Sci. 1985, 36, 2503–2508. [Google Scholar] [CrossRef] [PubMed]
- Ramsay, R.R.; Salach, J.I.; Dadgar, J.; Singer, T.P. Inhibition of Mitochondrial NADH Dehydrogenase by Pyridine Derivatives and Its Possible Relation to Experimental and Idiopathic Parkinsonism. Biochem. Biophys. Res. Commun. 1986, 135, 269–275. [Google Scholar] [CrossRef]
- Desai, V.G.; Feuers, R.J.; Hart, R.W.; Ali, S.F. MPP+-Induced Neurotoxicity in Mouse Is Age-Dependent: Evidenced by the Selective Inhibition of Complexes of Electron Transport. Brain Res. 1996, 715, 1–8. [Google Scholar] [CrossRef] [PubMed]
- Andreyev, A.Y.; Kushnareva, Y.E.; Starkov, A.A. Mitochondrial Metabolism of Reactive Oxygen Species. Biochemistry 2005, 70, 200–214. [Google Scholar] [CrossRef]
- Sherer, T.B.; Richardson, J.R.; Testa, C.M.; Seo, B.B.; Panov, A.V.; Yagi, T.; Matsuno-Yagi, A.; Miller, G.W.; Greenamyre, J.T. Mechanism of Toxicity of Pesticides Acting at Complex I: Relevance to Environmental Etiologies of Parkinson’s Disease. J. Neurochem. 2007, 100, 1469–1479. [Google Scholar] [CrossRef] [PubMed]
- Mizuno, Y.; Ohta, S.; Tanaka, M.; Takamiya, S.; Suzuki, K.; Sato, T.; Oya, H.; Ozawa, T.; Kagawa, Y. Deficiencies in Complex I Subunits of the Respiratory Chain in Parkinson’s Disease. Biochem. Biophys. Res. Commun. 1989, 163, 1450–1455. [Google Scholar] [CrossRef]
- Parker, W.D.; Parks, J.K.; Swerdlow, R.H. Complex I Deficiency in Parkinson’s Disease Frontal Cortex. Brain Res. 2008, 1189, 215–218. [Google Scholar] [CrossRef]
- Haas, R.H.; Nasirian, F.; Nakano, K.; Ward, D.; Pay, M.; Hill, R.; Shults, C.W. Low Platelet Mitochondrial Complex I and Complex II/III Activity in Early Untreated Parkinson’s Disease. Ann. Neurol. 1995, 37, 714–722. [Google Scholar] [CrossRef]
- Bindoff, L.A.; Birch-Machin, M.A.; Cartlidge, N.E.F.; Parker, W.D.; Turnbull, D.M. Respiratory Chain Abnormalities in Skeletal Muscle from Patients with Parkinson’s Disease. J. Neurol. Sci. 1991, 104, 203–208. [Google Scholar] [CrossRef]
- González-Rodríguez, P.; Zampese, E.; Stout, K.A.; Guzman, J.N.; Ilijic, E.; Yang, B.; Tkatch, T.; Stavarache, M.A.; Wokosin, D.L.; Gao, L.; et al. Disruption of Mitochondrial Complex I Induces Progressive Parkinsonism. Nature 2021, 599, 650–656. [Google Scholar] [CrossRef] [PubMed]
- Billingsley, K.J.; Barbosa, I.A.; Bandrés-Ciga, S.; Quinn, J.P.; Bubb, V.J.; Deshpande, C.; Botia, J.A.; Reynolds, R.H.; Zhang, D.; Simpson, M.A.; et al. Mitochondria Function Associated Genes Contribute to Parkinson’s Disease Risk and Later Age at Onset. NPJ Park. Dis. 2019, 5, 8. [Google Scholar] [CrossRef] [PubMed]
- Shimura, H.; Hattori, N.; Kubo, S.I.; Mizuno, Y.; Asakawa, S.; Minoshima, S.; Shimizu, N.; Iwai, K.; Chiba, T.; Tanaka, K.; et al. Familial Parkinson Disease Gene Product, Parkin, Is a Ubiquitin-Protein Ligase. Nat. Genet. 2000, 25, 302–305. [Google Scholar] [CrossRef] [PubMed]
- Lin, C.-C.; Yan, J.; Kapur, M.D.; Norris, K.L.; Hsieh, C.-W.; Huang, D.; Vitale, N.; Lim, K.-L.; Guan, Z.; Wang, X.-F.; et al. Parkin Coordinates Mitochondrial Lipid Remodeling to Execute Mitophagy. EMBO Rep. 2022, 23, e55191. [Google Scholar] [CrossRef]
- Ardah, M.T.; Radwan, N.; Khan, E.; Kitada, T.; Haque, M.E. Parkin Precipitates on Mitochondria via Aggregation and Autoubiquitination. Int. J. Mol. Sci. 2023, 24, 9027. [Google Scholar] [CrossRef]
- Machida, Y.; Chiba, T.; Takayanagi, A.; Tanaka, Y.; Asanuma, M.; Ogawa, N.; Koyama, A.; Iwatsubo, T.; Ito, S.; Jansen, P.H.; et al. Common Anti-Apoptotic Roles of Parkin and α-Synuclein in Human Dopaminergic Cells. Biochem. Biophys. Res. Commun. 2005, 332, 233–240. [Google Scholar] [CrossRef] [PubMed]
- Palacino, J.J.; Sagi, D.; Goldberg, M.S.; Krauss, S.; Motz, C.; Wacker, M.; Klose, J.; Shen, J. Mitochondrial Dysfunction and Oxidative Damage in Parkin-Deficient Mice. J. Biol. Chem. 2004, 279, 18614–18622. [Google Scholar] [CrossRef]
- Pesah, Y.; Pham, T.; Burgess, H.; Middlebrooks, B.; Verstreken, P.; Zhou, Y.; Harding, M.; Bellen, H.; Mardon, G. Drosophila Parkin Mutants Have Decreased Mass and Cell Size and Increased Sensitivity to Oxygen Radical Stress. Development 2004, 131, 2183–2194. [Google Scholar] [CrossRef]
- Greene, J.C.; Whitworth, A.J.; Kuo, I.; Andrews, L.A.; Feany, M.B.; Pallanck, L.J. Mitochondrial Pathology and Apoptotic Muscle Degeneration in Drosophila parkin Mutants. Proc. Natl. Acad. Sci. USA 2003, 100, 4078–4083. [Google Scholar] [CrossRef]
- Imaizumi, Y.; Okada, Y.; Akamatsu, W.; Koike, M.; Kuzumaki, N.; Hayakawa, H.; Nihira, T.; Kobayashi, T.; Ohyama, M.; Sato, S.; et al. Mitochondrial Dysfunction Associated with Increased Oxidative Stress and α-Synuclein Accumulation in PARK2 IPSC-Derived Neurons and Postmortem Brain Tissue. Mol. Brain 2012, 5, 35. [Google Scholar] [CrossRef]
- Shin, J.H.; Ko, H.S.; Kang, H.; Lee, Y.; Lee, Y.I.; Pletinkova, O.; Troconso, J.C.; Dawson, V.L.; Dawson, T.M. PARIS (ZNF746) Repression of PGC-1α Contributes to Neurodegeneration in Parkinson’s Disease. Cell 2011, 144, 689–702. [Google Scholar] [CrossRef] [PubMed]
- Stevens, D.A.; Lee, Y.; Kang, H.C.; Lee, B.D.; Lee, Y.I.; Bower, A.; Jiang, H.; Kang, S.U.; Andrabi, S.A.; Dawson, V.L.; et al. Parkin Loss Leads to Paris-Dependent Declines in Mitochondrial Mass and Respiration. Proc. Natl. Acad. Sci. USA 2015, 112, 11696–11701. [Google Scholar] [CrossRef] [PubMed]
- Chung, K.K.K.; Thomas, B.; Li, X.; Pletnikova, O.; Troncoso, J.C.; Marsh, L.; Dawson, V.L.; Dawson, T.M. S-Nitrosylation of Parkin Regulates Ubiquitination and Compromises Parkin’s Protective Function. Science 2004, 304, 1328–1331. [Google Scholar] [CrossRef] [PubMed]
- Yao, D.; Gu, Z.; Nakamura, T.; Shi, Z.Q.; Ma, Y.; Gaston, B.; Palmer, L.A.; Rockenstein, E.M.; Zhang, Z.; Masliah, E.; et al. Nitrosative Stress Linked to Sporadic Parkinson’s Disease: S-Nitrosylation of Parkin Regulates Its E3 Ubiquitin Ligase Activity. Proc. Natl. Acad. Sci. USA 2004, 101, 10810–10814. [Google Scholar] [CrossRef]
- LaVoie, M.J.; Ostaszewski, B.L.; Weihofen, A.; Schlossmacher, M.G.; Selkoe, D.J. Dopamine Covalently Modifies and Functionally Inactivates Parkin. Nat. Med. 2005, 11, 1214–1221. [Google Scholar] [CrossRef]
- Vandiver, M.S.; Paul, B.D.; Xu, R.; Karuppagounder, S.; Rao, F.; Snowman, A.M.; Seok Ko, H.; Il Lee, Y.; Dawson, V.L.; Dawson, T.M.; et al. Sulfhydration Mediates Neuroprotective Actions of Parkin. Nat. Commun. 2013, 4, 1626. [Google Scholar] [CrossRef]
- Jin, S.M.; Lazarou, M.; Wang, C.; Kane, L.A.; Narendra, D.P.; Youle, R.J. Mitochondrial Membrane Potential Regulates PINK1 Import and Proteolytic Destabilization by PARL. J. Cell Biol. 2010, 191, 933–942. [Google Scholar] [CrossRef]
- Matsuda, N.; Sato, S.; Shiba, K.; Okatsu, K.; Saisho, K.; Gautier, C.A.; Sou, Y.S.; Saiki, S.; Kawajiri, S.; Sato, F.; et al. PINK1 Stabilized by Mitochondrial Depolarization Recruits Parkin to Damaged Mitochondria and Activates Latent Parkin for Mitophagy. J. Cell Biol. 2010, 189, 211–221. [Google Scholar] [CrossRef]
- Yamano, K.; Youle, R.J. PINK1 Is Degraded through the N-End Rule Pathway. Autophagy 2013, 9, 1758–1769. [Google Scholar] [CrossRef]
- Narendra, D.P.; Jin, S.M.; Tanaka, A.; Suen, D.F.; Gautier, C.A.; Shen, J.; Cookson, M.R.; Youle, R.J. PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin. PLoS Biol. 2010, 8, e1000298. [Google Scholar] [CrossRef]
- Vives-Bauza, C.; Zhou, C.; Huang, Y.; Cui, M.; De Vries, R.L.A.; Kim, J.; May, J.; Tocilescu, M.A.; Liu, W.; Ko, H.S.; et al. PINK1-Dependent Recruitment of Parkin to Mitochondria in Mitophagy. Proc. Natl. Acad. Sci. USA 2010, 107, 378–383. [Google Scholar] [CrossRef] [PubMed]
- Koyano, F.; Okatsu, K.; Kosako, H.; Tamura, Y.; Go, E.; Kimura, M.; Kimura, Y.; Tsuchiya, H.; Yoshihara, H.; Hirokawa, T.; et al. Ubiquitin Is Phosphorylated by PINK1 to Activate Parkin. Nature 2014, 510, 162–166. [Google Scholar] [CrossRef] [PubMed]
- Lazarou, M.; Sliter, D.A.; Kane, L.A.; Sarraf, S.A.; Wang, C.; Burman, J.L.; Sideris, D.P.; Fogel, A.I.; Youle, R.J. The Ubiquitin Kinase PINK1 Recruits Autophagy Receptors to Induce Mitophagy. Nature 2015, 524, 309–314. [Google Scholar] [CrossRef] [PubMed]
- Wang, H.L.; Chou, A.H.; Yeh, T.H.; Li, A.H.; Chen, Y.L.; Kuo, Y.L.; Tsai, S.R.; Yu, S.T. PINK1 Mutants Associated with Recessive Parkinson’s Disease Are Defective in Inhibiting Mitochondrial Release of Cytochrome c. Neurobiol. Dis. 2007, 28, 216–226. [Google Scholar] [CrossRef] [PubMed]
- Zhou, Z.D.; Refai, F.S.; Xie, S.P.; Ng, S.H.; Chan, C.H.S.; Ho, P.G.H.; Zhang, X.D.; Lim, T.M.; Tan, E.K. Mutant PINK1 Upregulates Tyrosine Hydroxylase and Dopamine Levels, Leading to Vulnerability of Dopaminergic Neurons. Free Radic. Biol. Med. 2014, 68, 220–233. [Google Scholar] [CrossRef] [PubMed]
- Clark, I.E.; Dodson, M.W.; Jiang, C.; Cao, J.H.; Huh, J.R.; Seol, J.H.; Yoo, S.J.; Hay, B.A.; Guo, M. Drosophila Pink1 Is Required for Mitochondrial Function and Interacts Genetically with Parkin. Nature 2006, 441, 1162–1166. [Google Scholar] [CrossRef] [PubMed]
- Wang, H.L.; Chou, A.H.; Wu, A.S.; Chen, S.Y.; Weng, Y.H.; Kao, Y.C.; Yeh, T.H.; Chu, P.J.; Lu, C.S. PARK6 PINK1 Mutants Are Defective in Maintaining Mitochondrial Membrane Potential and Inhibiting ROS Formation of Substantia Nigra Dopaminergic Neurons. Biochim. Biophys. Acta (BBA)—Mol. Basis Dis. 2011, 1812, 674–684. [Google Scholar] [CrossRef] [PubMed]
- Gautier, C.A.; Kitada, T.; Shen, J. Loss of PINK1 Causes Mitochondrial Functional Defects and Increased Sensitivity to Oxidative Stress. Proc. Natl. Acad. Sci. USA 2008, 105, 11364–11369. [Google Scholar] [CrossRef]
- Yang, Y.; Ouyang, Y.; Yang, L.; Beal, M.F.; McQuibban, A.; Vogel, H.; Lu, B. Pink1 Regulates Mitochondrial Dynamics through Interaction with the Fission/Fusion Machinery. Proc. Natl. Acad. Sci. USA 2008, 105, 7070–7075. [Google Scholar] [CrossRef]
- Lee, M.J.; Chien, W.L.; Lee, T.R.; Hung, S.Y.; Kang, K.H.; Fu, W.M. Impairment of Oxidative Stress-Induced Heme Oxygenase-1 Expression by the Defect of Parkinson-Related Gene of PINK1. J. Neurochem. 2011, 117, 643–653. [Google Scholar] [CrossRef]
- Moisoi, N.; Fedele, V.; Edwards, J.; Martins, L.M. Loss of PINK1 Enhances Neurodegeneration in a Mouse Model of Parkinson’s Disease Triggered by Mitochondrial Stress. Neuropharmacology 2014, 77, 350–357. [Google Scholar] [CrossRef] [PubMed]
- Oliveras-Salvá, M.; Macchi, F.; Coessens, V.; Deleersnijder, A.; Gérard, M.; Van der Perren, A.; Van den Haute, C.; Baekelandt, V. Alpha-Synuclein-Induced Neurodegeneration Is Exacerbated in PINK1 Knockout Mice. Neurobiol. Aging 2014, 35, 2625–2636. [Google Scholar] [CrossRef] [PubMed]
- Gispert, S.; Brehm, N.; Weil, J.; Seidel, K.; Rüb, U.; Kern, B.; Walter, M.; Roeper, J.; Auburger, G. Potentiation of Neurotoxicity in Double-Mutant Mice with Pink1 Ablation and A53T-SNCA Overexpression. Hum. Mol. Genet. 2015, 24, 1061–1076. [Google Scholar] [CrossRef] [PubMed]
- Liu, J.; Wang, X.; Lu, Y.; Duan, C.; Gao, G.; Lu, L.; Yang, H. Pink1 Interacts with α-Synuclein and Abrogates α-Synuclein-Induced Neurotoxicity by Activating Autophagy. Cell Death Dis. 2017, 8, e3056. [Google Scholar] [CrossRef] [PubMed]
- Todd, A.M.; Staveley, B.E. Pink1 Suppresses α-Synuclein-Induced Phenotypes in a Drosophila Model of Parkinson’s Disease. Genome 2008, 51, 1040–1046. [Google Scholar] [CrossRef] [PubMed]
- Todd, A.M.; Staveley, B.E. Expression of Pink1 with α-Synuclein in the Dopaminergic Neurons of Drosophila Leads to Increases in Both Lifespan and Healthspan. Genet. Mol. Res. 2012, 11, 1497–1502. [Google Scholar] [CrossRef] [PubMed]
- Burchell, V.S.; Nelson, D.E.; Sanchez-Martinez, A.; Delgado-Camprubi, M.; Ivatt, R.M.; Pogson, J.H.; Randle, S.J.; Wray, S.; Lewis, P.A.; Houlden, H.; et al. The Parkinson’s Disease–Linked Proteins Fbxo7 and Parkin Interact to Mediate Mitophagy. Nat. Neurosci. 2013, 16, 1257–1265. [Google Scholar] [CrossRef] [PubMed]
- Fonzo, A.D.; Dekker, M.C.J.; Montagna, P.; Baruzzi, A.; Yonova, E.H.; Guedes, L.C.; Szczerbinska, A.; Zhao, T.; Dubbel-Hulsman, L.O.M.; Wouters, C.H.; et al. FBXO7 Mutations Cause Autosomal Recessive, Early-Onset Parkinsonian-Pyramidal Syndrome. Neurology 2009, 72, 240–245. [Google Scholar] [CrossRef]
- Sanchez-Martinez Id, A.; Martinez, A.; Whitworth Id, A.J. FBXO7/Ntc and USP30 Antagonistically Set the Ubiquitination Threshold for Basal Mitophagy and Provide a Target for Pink1 Phosphorylation in Vivo. PLoS Biol. 2023, 21, e3002244. [Google Scholar] [CrossRef]
- Kraus, F.; Goodall, E.A.; Smith, I.R.; Jiang, Y.; Paoli, J.C.; Adolf, F.; Zhang, J.; Paulo, J.A.; Schulman, B.A.; Harper, J.W. PARK15/FBXO7 Is Dispensable for PINK1/Parkin Mitophagy in INeurons and HeLa Cell Systems. EMBO Rep. 2023, 24, e56399. [Google Scholar] [CrossRef]
- Devi, L.; Raghavendran, V.; Prabhu, B.M.; Avadhani, N.G.; Anandatheerthavarada, H.K. Mitochondrial Import and Accumulation of α-Synuclein Impair Complex I in Human Dopaminergic Neuronal Cultures and Parkinson Disease Brain. J. Biol. Chem. 2008, 283, 9089–9100. [Google Scholar] [CrossRef] [PubMed]
- Chinta, S.J.; Mallajosyula, J.K.; Rane, A.; Andersen, J.K. Mitochondrial Alpha-Synuclein Accumulation Impairs Complex I Function in Dopaminergic Neurons and Results in Increased Mitophagy in Vivo. Neurosci. Lett. 2010, 486, 235. [Google Scholar] [CrossRef] [PubMed]
- Liu, G.; Zhang, C.; Yin, J.; Li, X.; Cheng, F.; Li, Y.; Yang, H.; Uéda, K.; Chan, P.; Yu, S. α-Synuclein Is Differentially Expressed in Mitochondria from Different Rat Brain Regions and Dose-Dependently down-Regulates Complex I Activity. Neurosci. Lett. 2009, 454, 187–192. [Google Scholar] [CrossRef] [PubMed]
- Hsu, L.J.; Sagara, Y.; Arroyo, A.; Rockenstein, E.; Sisk, A.; Mallory, M.; Wong, J.; Takenouchi, T.; Hashimoto, M.; Masliah, E. α-Synuclein Promotes Mitochondrial Deficit and Oxidative Stress. Am. J. Pathol. 2000, 157, 401–410. [Google Scholar] [CrossRef] [PubMed]
- Kamp, F.; Exner, N.; Lutz, A.K.; Wender, N.; Hegermann, J.; Brunner, B.; Nuscher, B.; Bartels, T.; Giese, A.; Beyer, K.; et al. Inhibition of Mitochondrial Fusion by α-Synuclein Is Rescued by PINK1, Parkin and DJ-1. EMBO J. 2010, 29, 3571. [Google Scholar] [CrossRef]
- Nakamura, K.; Nemani, V.M.; Azarbal, F.; Skibinski, G.; Levy, J.M.; Egami, K.; Munishkina, L.; Zhang, J.; Gardner, B.; Wakabayashi, J.; et al. Direct Membrane Association Drives Mitochondrial Fission by the Parkinson Disease-Associated Protein α-Synuclein. J. Biol. Chem. 2011, 286, 20710–20726. [Google Scholar] [CrossRef]
- Cole, N.B.; DiEuliis, D.; Leo, P.; Mitchell, D.C.; Nussbaum, R.L. Mitochondrial Translocation of α-Synuclein Is Promoted by Intracellular Acidification. Exp. Cell Res. 2008, 314, 2076–2089. [Google Scholar] [CrossRef]
- Choi, M.L.; Chappard, A.; Singh, B.P.; Maclachlan, C.; Rodrigues, M.; Fedotova, E.I.; Berezhnov, A.V.; De, S.; Peddie, C.J.; Athauda, D.; et al. Pathological Structural Conversion of α-Synuclein at the Mitochondria Induces Neuronal Toxicity. Nat. Neurosci. 2022, 25, 1134–1148. [Google Scholar] [CrossRef]
- Choubey, V.; Safiulina, D.; Vaarmann, A.; Cagalinec, M.; Wareski, P.; Kuum, M.; Zharkovsky, A.; Kaasik, A. Mutant A53T α-Synuclein Induces Neuronal Death by Increasing Mitochondrial Autophagy. J. Biol. Chem. 2011, 286, 10814–10824. [Google Scholar] [CrossRef]
- Martin, L.J.; Pan, Y.; Price, A.C.; Sterling, W.; Copeland, N.G.; Jenkins, N.A.; Price, D.L.; Lee, M.K. Parkinson’s Disease α-Synuclein Transgenic Mice Develop Neuronal Mitochondrial Degeneration and Cell Death. J. Neurosci. 2006, 26, 41–50. [Google Scholar] [CrossRef]
- Sumi-Akamaru, H.; Beck, G.; Shinzawa, K.; Kato, S.; Riku, Y.; Yoshida, M.; Fujimura, H.; Tsujimoto, Y.; Sakoda, S.; Mochizuki, H. High Expression of α-Synuclein in Damaged Mitochondria with PLA2G6 Dysfunction. Acta Neuropathol. Commun. 2016, 4, 27. [Google Scholar] [CrossRef] [PubMed]
- Bras, J.M.; Guerreiro, R.J.; Teo, J.T.H.; Darwent, L.; Vaughan, J.; Molloy, S.; Hardy, J.; Schneider, S.A. Atypical Parkinsonism-Dystonia Syndrome Caused by a Novel DJ1 Mutation. Mov. Disord. Clin. Pract. 2014, 1, 45–49. [Google Scholar] [CrossRef] [PubMed]
- Saito, Y. Oxidized DJ-1 as a Possible Biomarker of Parkinson’s Disease. J. Clin. Biochem. Nutr. 2014, 54, 138–144. [Google Scholar] [CrossRef] [PubMed]
- Saito, Y.; Hamakubo, T.; Yoshida, Y.; Ogawa, Y.; Hara, Y.; Fujimura, H.; Imai, Y.; Iwanari, H.; Mochizuki, Y.; Shichiri, M.; et al. Preparation and Application of Monoclonal Antibodies against Oxidized DJ-1. Significant Elevation of Oxidized DJ-1 in Erythrocytes of Early-Stage Parkinson Disease Patients. Neurosci. Lett. 2009, 465, 1–5. [Google Scholar] [CrossRef] [PubMed]
- Burbulla, L.F.; Song, P.; Mazzulli, J.R.; Zampese, E.; Wong, Y.C.; Jeon, S.; Santos, D.P.; Blanz, J.; Obermaier, C.D.; Strojny, C.; et al. Dopamine Oxidation Mediates Mitochondrial and Lysosomal Dysfunction in Parkinson’s Disease. Science 2017, 357, 1255–1261. [Google Scholar] [CrossRef] [PubMed]
- Imberechts, D.; Kinnart, I.; Wauters, F.; Terbeek, J.; Manders, L.; Wierda, K.; Eggermont, K.; Madeiro, R.F.; Sue, C.; Verfaillie, C.; et al. DJ-1 Is an Essential Downstream Mediator in PINK1/Parkin-Dependent. Brain 2022, 145, 4368–4384. [Google Scholar] [CrossRef]
- Irrcher, I.; Aleyasin, H.; Seifert, E.L.; Hewitt, S.J.; Chhabra, S.; Phillips, M.; Lutz, A.K.; Rousseaux, M.W.C.; Bevilacqua, L.; Jahani-Asl, A.; et al. Loss of the Parkinson’s Disease-Linked Gene DJ-1 Perturbs Mitochondrial Dynamics. Hum. Mol. Genet. 2010, 19, 3734–3746. [Google Scholar] [CrossRef]
- Heo, J.Y.; Park, J.H.; Kim, S.J.; Seo, K.S.; Han, J.S.; Lee, S.H.; Kim, J.M.; Park, J.I.; Park, S.K.; Lim, K.; et al. DJ-1 Null Dopaminergic Neuronal Cells Exhibit Defects in Mitochondrial Function and Structure: Involvement of Mitochondrial Complex I Assembly. PLoS ONE 2012, 7, e32629. [Google Scholar] [CrossRef]
- Funayama, M.; Ohe, K.; Amo, T.; Furuya, N.; Yamaguchi, J.; Saiki, S.; Li, Y.; Ogaki, K.; Ando, M.; Yoshino, H.; et al. CHCHD2 Mutations in Autosomal Dominant Late-Onset Parkinson’s Disease: A Genome-Wide Linkage and Sequencing Study. Lancet Neurol. 2015, 14, 274–282. [Google Scholar] [CrossRef]
- Lee, R.G.; Sedghi, M.; Salari, M.; Shearwood, A.-M.J.; Stentenbach, M.; Kariminejad, A.; Goullee, H.; Rackham, O.; Laing, N.G.; Tajsharghi, H.; et al. Early-Onset Parkinson Disease Caused by a Mutation in CHCHD2 and Mitochondrial Dysfunction. Neurol. Genet. 2018, 4, e276. [Google Scholar] [CrossRef]
- Aras, S.; Bai, M.; Lee, I.; Springett, R.; Hüttemann, M.; Grossman, L.I. MNRR1 (Formerly CHCHD2) Is a Bi-Organellar Regulator of Mitochondrial Metabolism. Mitochondrion 2015, 20, 43–51. [Google Scholar] [CrossRef]
- Liu, Y.; Clegg, H.V.; Leslie, P.L.; Di, J.; Tollini, L.A.; He, Y.; Kim, T.H.; Jin, A.; Graves, L.M.; Zheng, J.; et al. CHCHD2 Inhibits Apoptosis by Interacting with Bcl-x L to Regulate Bax Activation. Cell Death Differ. 2014, 22, 1035–1046. [Google Scholar] [CrossRef]
- Zhou, W.; Ma, D.; Sun, A.X.; Tran, H.-D.; Ma, D.; Singh, B.K.; Zhou, J.; Zhang, J.; Wang, D.; Zhao, Y.; et al. PD-Linked CHCHD2 Mutations Impair CHCHD10 and MICOS Complex Leading to Mitochondria Dysfunction. Hum. Mol. Genet. 2019, 28, 1100–1116. [Google Scholar] [CrossRef]
- Meng, H.; Yamashita, C.; Shiba-Fukushima, K.; Inoshita, T.; Funayama, M.; Sato, S.; Hatta, T.; Natsume, T.; Umitsu, M.; Takagi, J.; et al. Loss of Parkinson’s Disease-Associated Protein CHCHD2 Affects Mitochondrial Crista Structure and Destabilizes Cytochrome c. Nat. Commun. 2017, 8, 15500. [Google Scholar] [CrossRef]
- Fan, L.; Zhang, S.; Li, X.; Hu, Z.; Yang, J.; Zhang, S.; Zheng, H.; Su, Y.; Luo, H.; Liu, X.; et al. CHCHD2 p.Thr61Ile Knock-in Mice Exhibit Motor Defects and Neuropathological Features of Parkinson’s Disease. Brain Pathol. 2023, 33, e13124. [Google Scholar] [CrossRef]
- Nalls, M.A.; Pankratz, N.; Lill, C.M.; Do, C.B.; Hernandez, D.G.; Saad, M.; Destefano, A.L.; Kara, E.; Bras, J.; Sharma, M.; et al. Large-Scale Meta-Analysis of Genome-Wide Association Data Identifies Six New Risk Loci for Parkinson’s Disease. Nat. Genet. 2014, 46, 989–993. [Google Scholar] [CrossRef]
- Lesage, S.; Drouet, V.; Majounie, E.; Deramecourt, V.; Jacoupy, M.; Nicolas, A.; Cormier-Dequaire, F.; Hassoun, S.M.; Pujol, C.; Ciura, S.; et al. Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy. Am. J. Hum. Genet. 2016, 98, 500–513. [Google Scholar] [CrossRef]
- Gu, X.; Li, C.; Chen, Y.; Ou, R.; Cao, B.; Wei, Q.; Hou, Y.; Zhang, L.; Song, W.; Zhao, B.; et al. Mutation Screening and Burden Analysis of VPS13C in Chinese Patients with Early-Onset Parkinson’s Disease. Neurobiol. Aging 2020, 94, 311.e1–311.e4. [Google Scholar] [CrossRef]
- Miliotis, S.; Nicolalde, B.; Ortega, M.; Yepez, J.; Caicedo, A. Forms of Extracellular Mitochondria and Their Impact in Health. Mitochondrion 2019, 48, 16–30. [Google Scholar] [CrossRef]
- Rustom, A.; Saffrich, R.; Markovic, I.; Walther, P.; Gerdes, H.H. Nanotubular Highways for Intercellular Organelle Transport. Science 2004, 303, 1007–1010. [Google Scholar] [CrossRef]
- Jackson, M.V.; Morrison, T.J.; Doherty, D.F.; McAuley, D.F.; Matthay, M.A.; Kissenpfennig, A.; O’Kane, C.M.; Krasnodembskaya, A.D. Mitochondrial Transfer via Tunneling Nanotubes Is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS. Stem Cells 2016, 34, 2210–2223. [Google Scholar] [CrossRef]
- Phinney, D.G.; Di Giuseppe, M.; Njah, J.; Sala, E.; Shiva, S.; St Croix, C.M.; Stolz, D.B.; Watkins, S.C.; Di, Y.P.; Leikauf, G.D.; et al. Mesenchymal Stem Cells Use Extracellular Vesicles to Outsource Mitophagy and Shuttle MicroRNAs. Nat. Commun. 2015, 6, 8472. [Google Scholar] [CrossRef]
- Melentijevic, I.; Toth, M.L.; Arnold, M.L.; Guasp, R.J.; Harinath, G.; Nguyen, K.C.; Taub, D.; Parker, J.A.; Neri, C.; Gabel, C.V.; et al. C. elegans Neurons Jettison Protein Aggregates and Mitochondria under Neurotoxic Stress. Nature 2017, 542, 367–371. [Google Scholar] [CrossRef]
- Davis, C.H.O.; Kim, K.Y.; Bushong, E.A.; Mills, E.A.; Boassa, D.; Shih, T.; Kinebuchi, M.; Phan, S.; Zhou, Y.; Bihlmeyer, N.A.; et al. Transcellular Degradation of Axonal Mitochondria. Proc. Natl. Acad. Sci. USA 2014, 111, 9633–9638. [Google Scholar] [CrossRef]
- Morales, I.; Sanchez, A.; Puertas-Avendaño, R.; Rodriguez-Sabate, C.; Perez-Barreto, A.; Rodriguez, M. Neuroglial Transmitophagy and Parkinson’s Disease. Glia 2020, 68, 2277–2299. [Google Scholar] [CrossRef]
- Thurairajah, K.; Briggs, G.D.; Balogh, Z.J. The Source of Cell-Free Mitochondrial DNA in Trauma and Potential Therapeutic Strategies. Eur. J. Trauma Emerg. Surg. 2018, 44, 325–334. [Google Scholar] [CrossRef]
- Gu, X.; Wu, G.; Yao, Y.; Zeng, J.; Shi, D.; Lv, T.; Luo, L.; Song, Y. Intratracheal Administration of Mitochondrial DNA Directly Provokes Lung Inflammation through the TLR9-P38 MAPK Pathway. Free Radic. Biol. Med. 2015, 83, 149–158. [Google Scholar] [CrossRef]
- Xie, L.; Liu, S.; Cheng, J.; Wang, L.; Liu, J.; Gong, J. Exogenous Administration of Mitochondrial DNA Promotes Ischemia Reperfusion Injury via TLR9-P38 MAPK Pathway. Regul. Toxicol. Pharmacol. 2017, 89, 148–154. [Google Scholar] [CrossRef]
- Peng, Y.; Zheng, D.; Zhang, X.; Pan, S.; Ji, T.; Zhang, J.; Shen, H.Y.; Wang, H.H. Cell-Free Mitochondrial DNA in the CSF: A Potential Prognostic Biomarker of Anti-NMDAR Encephalitis. Front. Immunol. 2019, 10, 430102. [Google Scholar] [CrossRef]
- Varhaug, K.N.; Vedeler, C.A.; Myhr, K.M.; Aarseth, J.H.; Tzoulis, C.; Bindoff, L.A. Increased Levels of Cell-Free Mitochondrial DNA in the Cerebrospinal Fluid of Patients with Multiple Sclerosis. Mitochondrion 2017, 34, 32–35. [Google Scholar] [CrossRef]
- Podlesniy, P.; Figueiro-Silva, J.; Llado, A.; Antonell, A.; Sanchez-Valle, R.; Alcolea, D.; Lleo, A.; Molinuevo, J.L.; Serra, N.; Trullas, R. Low Cerebrospinal Fluid Concentration of Mitochondrial DNA in Preclinical Alzheimer Disease. Ann. Neurol. 2013, 74, 655–668. [Google Scholar] [CrossRef]
- Cervera-Carles, L.; Alcolea, D.; Estanga, A.; Ecay-Torres, M.; Izagirre, A.; Clerigué, M.; García-Sebastián, M.; Villanúa, J.; Escalas, C.; Blesa, R.; et al. Cerebrospinal Fluid Mitochondrial DNA in the Alzheimer’s Disease Continuum. Neurobiol. Aging 2017, 53, 192.e1–192.e4. [Google Scholar] [CrossRef]
- Lowes, H.; Pyle, A.; Santibanez-Koref, M.; Hudson, G. Circulating Cell-Free Mitochondrial DNA Levels in Parkinson’s Disease Are Influenced by Treatment. Mol. Neurodegener. 2020, 15, 10. [Google Scholar] [CrossRef]
- Shi, X.; Zhao, M.; Fu, C.; Fu, A. Intravenous Administration of Mitochondria for Treating Experimental Parkinson’s Disease. Mitochondrion 2017, 34, 91–100. [Google Scholar] [CrossRef]
- Chang, J.C.; Wu, S.L.; Liu, K.H.; Chen, Y.H.; Chuang, C.S.; Cheng, F.C.; Su, H.L.; Wei, Y.H.; Kuo, S.J.; Liu, C.S. 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.e3. [Google Scholar] [CrossRef]
- Chang, J.C.; Chao, Y.C.; Chang, H.S.; Wu, Y.L.; Chang, H.J.; Lin, Y.S.; Cheng, W.L.; Lin, T.T.; Liu, C.S. Intranasal Delivery of Mitochondria for Treatment of Parkinson’s Disease Model Rats Lesioned with 6-Hydroxydopamine. Sci. Rep. 2021, 11, 10597. [Google Scholar] [CrossRef]
- Cheng, X.Y.; Biswas, S.; Li, J.; Mao, C.J.; Chechneva, O.; Chen, J.; Li, K.; Li, J.; Zhang, J.R.; Liu, C.F.; et al. Human IPSCs Derived Astrocytes Rescue Rotenone-Induced Mitochondrial Dysfunction and Dopaminergic Neurodegeneration in Vitro by Donating Functional Mitochondria. Transl. Neurodegener. 2020, 9, 13. [Google Scholar] [CrossRef]
- Prasuhn, J.; Davis, R.L.; Kumar, K.R. Targeting Mitochondrial Impairment in Parkinson’s Disease: Challenges and Opportunities. Front. Cell Dev. Biol. 2021, 8, 615461. [Google Scholar] [CrossRef]
PARK | Gene | Protein | Form | Clinical Features | Mitochondrial-Related Functions |
---|---|---|---|---|---|
PARK1 PARK4 | SNCA | Alpha synuclein (αSyn) | Autosomal dominant | Range from early-onset PD with rapid progression and severe non-motor symptoms including cognitive decline and autonomic dysfunction to classical PD |
|
PARK2 | PRKN | Parkin (E3 ubiquitin ligase) | Autosomal recessive | Early-juvenile onset, slow progression, frequent dyskinesia/dystonia |
|
PARK6 | PINK1 | PTEN-induced putative kinase 1 (mitochondrial serine/threonine protein kinase) | Autosomal recessive | Early onset, slow progression |
|
PARK7 | DJ-1 | Protein/nucleic acid deglycase | Autosomal recessive | Early onset, slow progression, dystonia, psychiatric symptoms |
|
PARK15 | FBXO7 | F-box protein 7 | Autosomal recessive | Early onset with atypical features (pyramidal signs) |
|
PARK22 | CHCHD2 | Coiled-coil-helix-coiled-coil-helix domain 2 | Autosomal recessive/ dominant | Early onset/late onset |
|
PARK23 | VPS13C | Vacuolar protein sorting-associated protein 13C | Autosomal recessive | Early onset, rapid progression, early cognitive decline, widely distributed Lewy bodies |
|
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Choong, C.-J.; Mochizuki, H. Involvement of Mitochondria in Parkinson’s Disease. Int. J. Mol. Sci. 2023, 24, 17027. https://doi.org/10.3390/ijms242317027
Choong C-J, Mochizuki H. Involvement of Mitochondria in Parkinson’s Disease. International Journal of Molecular Sciences. 2023; 24(23):17027. https://doi.org/10.3390/ijms242317027
Chicago/Turabian StyleChoong, Chi-Jing, and Hideki Mochizuki. 2023. "Involvement of Mitochondria in Parkinson’s Disease" International Journal of Molecular Sciences 24, no. 23: 17027. https://doi.org/10.3390/ijms242317027