Abstract
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. The exact causes of neuronal damage are unknown, but mounting evidence indicates that mitochondrial-mediated pathways contribute to the underlying mechanisms of dopaminergic neuronal cell death both in PD patients and in PD animal models. Mitochondria are organized in a highly dynamic tubular network that is continuously reshaped by opposing processes of fusion and fission. Defects in either fusion or fission, leading to mitochondrial fragmentation, limit mitochondrial motility, decrease energy production and increase oxidative stress, thereby promoting cell dysfunction and death. Thus, the regulation of mitochondrial dynamics processes, such as fusion, fission and mitophagy, represents important mechanisms controlling neuronal cell fate. In this review, we summarize some of the recent evidence supporting that impairment of mitochondrial dynamics, mitophagy and mitochondrial import occurs in cellular and animal PD models and disruption of these processes is a contributing mechanism to cell death in dopaminergic neurons. We also summarize mitochondria-targeting therapeutics in models of PD, proposing that modulation of mitochondrial impairment might be beneficial for drug development toward treatment of PD.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting over 1% of the population older than 60 years of age
We propose a causal role for mitochondrial dysfunction in the development of PD, because (1) neurotoxins causing parkinsonism, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, paraquat, induce dopaminergic neuronal death through direct inhibition of mitochondrial complex I
Accumulating evidence supports the hypothesis that mitochondrial abnormalities and dysfunction could critically influence neuronal degeneration in both sporadic and faimilial PD
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting over 1% of the population older than 60 years of age. Despite a large number of studies on the pathogenesis of PD, there is still inconclusive evidence about why dopaminergic neurons are selectively degenerated. Among a number of proposed mechanisms involved in PD pathogenesis, mitochondrial dysfunction has been repeatedly implicated as the cause of the death of DA neurons in PD [2,3,4,5]. We propose a causal role for mitochondrial dysfunction in the development of PD, because (1) neurotoxins causing parkinsonism, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, paraquat, induce dopaminergic neuronal death through direct inhibition of mitochondrial complex I activity; (2) mutant proteins from PD-related genes associate with mitochondria where they elicit diverse mitochondrial dysregulation and subsequently cause neuronal degeneration; (3) therapeutic agents that target mitochondrial protein or inhibit mitochondrial damage can reduce neuropathological phenotypes of PD in animal models and cells from PD patients
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