The mitochondrial kinase PINK1, stress response and Parkinson's disease.
Mitochondrial dysfunction is well documented in presymptomatic brain tissue with Parkinson's disease (PD). Identification of the autosomal recessive variant PARK6 caused by loss-of-function mutations in the mitochondrial kinase PINK1 provides an opportunity to dissect pathogenesis. Although PARK6 shows clinical differences to PD, the induction of alpha-synuclein "Lewy" pathology by PINK1-deficiency proves that mitochondrial pathomechanisms are relevant for old-age PD. Mitochondrial dysfunction is induced by PINK1 deficiency even in peripheral tissues unaffected by disease, consistent with the ubiquitous expression of PINK1. It remains unclear whether this dysfunction is due to PINK1-mediated phosphorylation of proteins inside or outside mitochondria. Although PINK1 deficiency affects the mitochondrial fission/fusion balance, cell stress is required in mammals to alter mitochondrial dynamics and provoke apoptosis. Clearance of damaged mitochondria depends on pathways including PINK1 and Parkin and is critical for postmitotic neurons with high energy demand and cumulative stress, providing a mechanistic concept for the tissue specificity of disease.
Jendrach
Marina
M
Klinik für Neurologie, Goethe Universität, Haus 89, Heinrich-Hoffmann-Str. 7, 60590, Frankfurt/M, Germany.
Gispert
Suzana
S
Ricciardi
Filomena
F
Klinkenberg
Michael
M
Schemm
Rudolf
R
Auburger
Georg
G
D000818:Animals; D006801:Humans; D008928:Mitochondria / Q000473:pathology; D024101:Mitochondrial Proteins / Q000502:physiology; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D011494:Protein Kinases / Q000172:deficiency* / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology; D000099202:PTEN-Induced Putative Kinase
D024101:Mitochondrial Proteins; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein