Mitochondrial mechanisms in PD
Mitochondria are strongly associated with both monogenic and idiopathic PD, but their role in the disease is poorly understood. The overarching goal of our mitochondrial research is to advance the understanding of how altered mitochondrial structure and function contribute to PD and to exploit this knowledge to improve patient diagnosis and treatment.
The first indication that mitochondrial impairment may be involved in PD came in 1983, with the discovery that the compound MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), an inhibitor of the mitochondrial respiratory complex I, causes loss of the dopaminergic SNc neurons and parkinsonism in humans1. Other complex I inhibitors, including the pesticide rotenone, were also shown to have a predilection for damaging the dopaminergic neurons of the SNc, and to cause parkinsonism, and even Lewy-like pathology, in animals2.
The dopaminergic SNc is also vulnerable to mitochondrial impairment of genetic etiology. Mutations in genes involved in mitochondrial quality-control and mitophagy (e.g., PRKN, PINK1, DJ1) cause autosomal recessive forms of monogenic PD3. Moreover, we and others have shown that mutations in genes regulating mtDNA maintenance (e.g., POLG, TWNK)4–6 and mitochondrial dynamics (e.g., OPA1)7, cause severe degeneration of the dopaminergic SNc – with or without accompanying clinical parkinsonian features.
A growing body of evidence indicates that mitochondrial pathology occurs in individuals with idiopathic PD. MRC deficiencies, primarily affecting complex I, accumulate in the dopaminergic neurons of the SNc with age and have been shown to be more pronounced in PD8,9. It has been proposed that these deficiencies may be caused by the age-dependent accumulation of mtDNA deletions in dopaminergic neurons10,11. We have shown that mtDNA maintenance is impaired in the dopaminergic SNc neurons of individuals with idiopathic PD, causing gradual loss of wild-type mtDNA12. While the aetiology of impaired mtDNA homeostasis in PD remains largely unknown, previous findings by our group suggest that this may be partly primed by inherited polygenic variation in genes encoding the mtDNA homeosome13.
Whether mitochondrial dysfunction occurs and/or contributes to neurodegeneration outside the dopaminergic SNc in PD remain largely unsettled questions. Our previous work indicates that neuronal complex I deficiency is not limited to the SNc, but can occur throughout multiple regions of the PD brain14. When collectively examined, however, current evidence is highly variable and, in part, conflicting15. Studies in extraneural tissues, such as skeletal muscle, platelets, and lymphocytes, have been even more contradictory, with some finding robust evidence of MRC changes, and others detecting no abnormalities15. Thus, the role and anatomical extent of mitochondrial pathology in idiopathic PD remain poorly understood and/or incompletely characterized.
Our ongoing research aims to:
- Identify the aetiology and pathogenesis of mitochondrial dysfunction in PD, with a focus on mtDNA and the MRC.
- Elucidate the downstream effects of MRC dysfunction in PD and whether/how this contributes to neurodegeneration and disease initiation and progression.
- Study the pervasiveness of mitochondrial dysfunction in PD and identify mitochondria-based biomarkers for improved diagnosis, monitoring, and evaluation of treatment responses.
- Translate specific aspects of mitochondrial dysfunction into therapeutic targets and develop and test tailored therapies for patients.
- Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983;219(4587):979–980.
- De Miranda BR, Van Houten B, Sanders LH. Toxin-Mediated Complex I Inhibition and Parkinson’s Disease [Internet]. In: Buhlman LM, editor. Mitochondrial Mechanisms of Degeneration and Repair in Parkinson’s Disease. Cham: Springer International Publishing; 2016 p. 115–137.[cited 2020 May 23 ] Available from: https://doi.org/10.1007/978-3-319-42139-1_6
- Deng H, Wang P, Jankovic J. The genetics of Parkinson disease. Ageing Res Rev 2018;42:72–85.
- Tzoulis C, Tran GT, Schwarzlmüller T, et al. Severe nigrostriatal degeneration without clinical parkinsonism in patients with polymerase gamma mutations. Brain 2013;136(8):2393–2404.
- Tzoulis C, Schwarzlmuller T, Biermann M, et al. Mitochondrial DNA homeostasis is essential for nigrostriatal integrity. Mitochondrion 2016;28:33–7.
- Palin EJ, Paetau A, Suomalainen A. Mesencephalic complex I deficiency does not correlate with parkinsonism in mitochondrial DNA maintenance disorders. Brain : a journal of neurology 2013;136(Pt 8):2379–92.
- Carelli V, Musumeci O, Caporali L, et al. Syndromic parkinsonism and dementia associated with OPA1 missense mutations [Internet]. Annals of neurology 2015;Available from: http://www.ncbi.nlm.nih.gov/pubmed/25820230
- Schapira AH, Cooper JM, Dexter D, et al. Mitochondrial complex I deficiency in Parkinson’s disease. Lancet 1989;1(8649):1269.
- Hattori N, Tanaka M, Ozawa T, Mizuno Y. Immunohistochemical studies on complexes I, II, III, and IV of mitochondria in Parkinson’s disease. Ann. Neurol. 1991;30(4):563–571.
- Bender A, Krishnan KJ, Morris CM, et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nature genetics 2006;38(5):515–7.
- Kraytsberg Y, Kudryavtseva E, McKee AC, et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nature genetics 2006;38(5):518–20.
- Dölle C, Flønes I, Nido GS, et al. Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease. Nat Commun 2016;7(1):13548.
- Gaare JJ, Nido GS, Sztromwasser P, et al. Rare genetic variation in mitochondrial pathways influences the risk for Parkinson’s disease: Mitochondrial Pathways In PD. Mov Disord. 2018;33(10):1591–1600.
- Flønes IH, Fernandez-Vizarra E, Lykouri M, et al. Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage. Acta Neuropathol 2018;135(3):409–425.
- Subrahmanian N, LaVoie MJ. Is there a special relationship between complex I activity and nigral neuronal loss in Parkinson’s disease? A critical reappraisal. Brain Research 2021;147434.