Akt mediated mitochondrial protection in the heart: metabolic and survival pathways to the rescue.
Cardiomyocyte death is now recognized as a critical factor in the development of heart disease. Mitochondria are not only responsible for energy production to ensure that cardiac output meets the body's energy demands, but they serve as critical integrators of cell survival signals. Numerous stressors are known to induce cell death by necrosis and/or apoptosis mediated through mitochondrial dysregulation. Anti- and pro-apoptotic Bcl-2 family proteins regulate apoptosis by controlling mitochondrial outer membrane permeability, whereas opening of the mitochondrial permeability transition pore (PT-pore) induces large amplitude permeability of the inner membrane and consequent rupture of the outer membrane. Akt is one of the best described survival kinases activated by receptor ligands and its activation preserves mitochondrial integrity and protects cardiomyocytes against necrotic and apoptotic death. The mechanisms responsible for Akt-mediated mitochondrial protection have not been fully elucidated. There is, however, accumulating evidence that multiple Akt target molecules, recruited through both transcriptional and post-transcriptional mechanisms, directly impinge upon and protect mitochondria. In this review we discuss mechanisms by which Akt activation can effect changes at the mitochondria that protect cardiomyocytes and attenuate pathophysiological responses of the heart.
Department of Pharmacology, University of California, 9500 Gilman Dr., La Jolla, San Diego, CA 92093-0636, USA. smiyamoto@ucsd.edu
Shigeki
S
Miyamoto
Anne N
AN
Murphy
Joan Heller
JH
Brown
D000818:Animals; D017209:Apoptosis; D002463:Cell Membrane Permeability; D002470:Cell Survival; D004789:Enzyme Activation; D006801:Humans; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D051336:Mitochondrial Membranes; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D009336:Necrosis; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D014158:Transcription, Genetic
D019253:Proto-Oncogene Proteins c-bcl-2; D051058:Oncogene Protein v-akt