Mitochondrial quality control: insights on how Parkinson's disease related genes PINK1, parkin, and Omi/HtrA2 interact to maintain mitochondrial homeostasis.
Alterations in mitochondrial homeostasis have been implicated in the etiology of Parkinson disease (PD) as demonstrated by human tissue studies, cell culture and in vivo genetic and toxin models. Mutations in the genes encoding PTEN-induced kinase 1 (PINK1), Omi/HtrA2 and parkin contribute to rare forms of parkinsonian neurodegeneration. Recently, each of these proteins has been shown to play a normal role in regulating mitochondrial structure, function, fission-fusion dynamics, or turnover (autophagy and biogenesis), promoting neuronal survival. Here, we review the biochemical mechanisms of mitochondrial protection conferred by each of these PD associated gene products in neurons, neuronal cell lines and other cell types. Potential molecular interactions and mitoprotective signaling pathways involving these three PD associated gene products are discussed in the context of mitochondrial quality control, in response to increasing levels of mitochondrial damage. We propose that PINK1, Omi/HtrA2 and parkin participate at different levels in mitochondrial quality control, converging through some overlapping and some distinct steps to maintain a common phenotype of healthy mitochondrial networks.
Dagda
Ruben K
RK
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Chu
Charleen T
CT
D000074923:High-Temperature Requirement A Serine Peptidase 2; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology*; D011494:Protein Kinases / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D000099202:PTEN-Induced Putative Kinase
D000074923:High-Temperature Requirement A Serine Peptidase 2; D024101:Mitochondrial Proteins; D011494:Protein Kinases; D012697:Serine Endopeptidases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C000615914:HTRA2 protein, human