Mitochondrial homeostasis in Parkinson's disease - a triumvirate rule?

Chee-Hoe Ng; Liting Hang; Kah-Leong Lim

doi:10.4103/1673-5374.213546

摘要：Mitochondrial dysfunction in Parkinson's disease: Mito-chondria are the primary energy generator of the cell and they are important for cell survival and apoptosis. Defec-tive mitochondrial homeostasis is frequently reported in human diseases especially those affecting the brain. Parkinson's disease (PD), a prevalent neurodegenerative disorder where patients progressively loss control of their movements, is linked to mitochondrial dysfunction. A9-type dopaminergic (DA) neurons in the substantia nigra pars compacta, are significantly diminished in PD brains. These neurons are known to be more susceptible to oxi-dative stress and mitochondrial toxins compared to other neuronal subtypes. Indeed, exposure to herbicides and pesticides such as paraquat and rotenone are linked to sporadic PD and represents a popular strategy to generate animal models of PD. Furthermore, studies carried out in induced pluripotent stem cells (iPSCs) confirmed the rel-evance of mitochondrial dysfunction and oxidative stress in PD. Interestingly, familial PD cases are linked to genes with apparent diverse functions that nonetheless converge towards the mitochondrion. These PD-linked genes inter-act closely with each other through their participations in pathways necessary for the maintenance of mitochondrial homeostasis. For example, α-synuclein (α-syn) and leu-cine-rich repeat kinase 2 (LRRK2) could regulate mito-chondrial fission/fusion. DJ-1, an oxidative stress sensor and protease, localizes to the mitochondria during oxida-tive stress. The ubiquitin ligase Parkin and mitochondrial serine kinase PTEN-induced putative kinase 1 (PINK1) collaborate to execute mitochondrial quality control through mitophagy, a process whereby damaged mito-chondria are removed selectively. The mitochondrial ser-ine protease high temperature requirement A2 [(HtrA2)/Omi] protein acts downstream of PINK1 but in a pathway parallel to Parkin. Interestingly, aberrant mitochondrial fragmentation is often associated with autosomal dom-inant Parkinsonism caused by mutations in α-syn and LRRK2. On the other hand, autosomal recessive mutations of Parkin, PINK1, DJ-1 and ATPase type 13A2 (ATP13a2) tend to give rise to mitochondrial swelling phenotypes. In essence, we could appreciate the intimate relationship between mitochondrial dysfunction and PD pathogenesis. Given this, unravelling the mechanisms underlying mito-chondrial abnormalities holds promise to enhance our un-derstanding of the disease etiology and the development of effective treatment strategies for PD.