Role for mitochondrial oxidants as regulators of cellular metabolism.
Leakage of mitochondrial oxidants contributes to a variety of harmful conditions ranging from neurodegenerative diseases to cellular senescence. We describe here, however, a physiological and heretofore unrecognized role for mitochondrial oxidant release. Mitochondrial metabolism of pyruvate is demonstrated to activate the c-Jun N-terminal kinase (JNK). This metabolite-induced rise in cytosolic JNK1 activity is shown to be triggered by increased release of mitochondrial H(2)O(2). We further demonstrate that in turn, the redox-dependent activation of JNK1 feeds back and inhibits the activity of the metabolic enzymes glycogen synthase kinase 3beta and glycogen synthase. As such, these results demonstrate a novel metabolic regulatory pathway activated by mitochondrial oxidants. In addition, they suggest that although chronic oxidant production may have deleterious effects, mitochondrial oxidants can also function acutely as signaling molecules to provide communication between the mitochondria and the cytosol.
Nemoto
S
S
Laboratory of Molecular Biology, National Heart Lung and Blood Institute, NIH, Bethesda, Maryland 20892, USA.
Takeda
K
K
Yu
Z X
ZX
Ferrans
V J
VJ
Finkel
T
T
D016475:3T3 Cells / Q000378:metabolism; D000818:Animals; D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D005246:Feedback; D006006:Glycogen Synthase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D007668:Kidney / Q000196:embryology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000196:embryology; D009363:Neoplasm Proteins / Q000378:metabolism; D016877:Oxidants / Q000502:physiology*; D010084:Oxidation-Reduction; D019289:Pyruvic Acid / Q000378:metabolism / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000502:physiology; D014471:Umbilical Veins
D009363:Neoplasm Proteins; D016877:Oxidants; D017382:Reactive Oxygen Species; C032456:antimycin; D000968:Antimycin A; D019289:Pyruvic Acid; D006861:Hydrogen Peroxide; D006006:Glycogen Synthase; D038341:Glycogen Synthase Kinases; D019893:Ribosomal Protein S6 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3