Mitochondrial translocation of alpha-synuclein is promoted by intracellular acidification.
Mitochondrial dysfunction plays a central role in the selective vulnerability of dopaminergic neurons in Parkinson's disease (PD) and is influenced by both environmental and genetic factors. Expression of the PD protein alpha-synuclein or its familial mutants often sensitizes neurons to oxidative stress and to damage by mitochondrial toxins. This effect is thought to be indirect, since little evidence physically linking alpha-synuclein to mitochondria has been reported. Here, we show that the distribution of alpha-synuclein within neuronal and non-neuronal cells is dependent on intracellular pH. Cytosolic acidification induces translocation of alpha-synuclein from the cytosol onto the surface of mitochondria. Translocation occurs rapidly under artificially-induced low pH conditions and as a result of pH changes during oxidative or metabolic stress. Binding is likely facilitated by low pH-induced exposure of the mitochondria-specific lipid cardiolipin. These results imply a direct role for alpha-synuclein in mitochondrial physiology, especially under pathological conditions, and in principle, link alpha-synuclein to other PD genes in regulating mitochondrial homeostasis.
Cole
Nelson B
NB
Genetic Diseases Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ncole@mail.nih.gov
Dieuliis
Diane
D
Leo
Paul
P
Mitchell
Drake C
DC
Nussbaum
Robert L
RL
D000963:Antimetabolites / Q000378:metabolism; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000378:metabolism; D002460:Cell Line; D003847:Deoxyglucose / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000648:ultrastructure; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D019810:Sodium Azide / Q000378:metabolism; D014475:Uncoupling Agents / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D000963:Antimetabolites; D004791:Enzyme Inhibitors; D016877:Oxidants; D014475:Uncoupling Agents; D051844:alpha-Synuclein; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D019810:Sodium Azide; D003847:Deoxyglucose; D006861:Hydrogen Peroxide