Cell metabolism affects selective vulnerability in PINK1-associated Parkinson's disease.
Mitochondrial dysfunction plays a primary role in the pathogenesis of Parkinson's disease (PD), particularly in autosomal recessive forms of the disease caused by mutations encoding PINK1. Although mitochondrial pathology can be demonstrated in many cell types, it is neurons that bear the brunt of cell death in PD. We studied the mitochondrial physiology of neurons and muscle cells with loss of function of the nuclear encoded mitochondrial protein PINK1. PINK1 is widely expressed in many types of tissues, but deficiency selectively induces death in neurons. We report here that the same genetic defect results in opposing phenotypes in different cell types, depending on the metabolic properties of the cell. Thus, PINK1-deficient myocytes exhibit high basal mitochondrial membrane potential (Δψm), whereas PINK1-deficient neurons have been shown to exhibit a low Δψm. PINK1 deficiency induces impaired respiration in both cell types, with a concomitant increase in glycolytic activity. We demonstrate that the high glycolytic capacity in myocytes compared with neurons enables them to produce more ATP and, therefore, compensates for the metabolic defects induced by PINK1 deficiency. Furthermore, the high Δψm generated in PINK1 knockout (KO) muscle mitochondria enables them to buffer cytosolic Ca(2+) fluxes, rendering them resistant to Ca(2+) stress effectively. Conversely, PINK1 KO neurons were previously shown to develop mitochondrial Ca(2+) overload and Ca(2+)-induced mitochondrial depolarisation. Prevention of Ca(2+) dysregulation in myocytes might therefore account for the sparing of these cells in PD.
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG,  UK.
Zhi
Z
Yao
Sonia
S
Gandhi
Victoria S
VS
Burchell
Helene
H
Plun-Favreau
Nicholas W
NW
Wood
Andrey Y
AY
Abramov
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D019069:Cell Respiration; D002478:Cells, Cultured; D005347:Fibroblasts / Q000502:physiology; D055786:Gene Knockout Techniques; D006019:Glycolysis; D053078:Membrane Potential, Mitochondrial; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D010085:Oxidative Phosphorylation; D010300:Parkinson Disease / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics*; D000099202:PTEN-Induced Putative Kinase
D000255:Adenosine Triphosphate; D002118:Calcium; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase