Gating of the mitochondrial permeability transition pore by long chain fatty acyl analogs in vivo.
The role played by long chain fatty acids (LCFA) in promoting energy expenditure is confounded by their dual function as substrates for oxidation and as putative classic uncouplers of mitochondrial oxidative phosphorylation. LCFA analogs of the MEDICA (MEthyl-substituted DICarboxylic Acids) series are neither esterified into lipids nor beta-oxidized and may thus simulate the uncoupling activity of natural LCFA in vivo, independently of their substrate role. Treatment of rats or cell lines with MEDICA analogs results in low conductance gating of the mitochondrial permeability transition pore (PTP), with 10-40% decrease in the inner mitochondrial membrane potential. PTP gating by MEDICA analogs is accounted for by inhibition of Raf1 expression and kinase activity, resulting in suppression of the MAPK/RSK1 and the adenylate cyclase/PKA transduction pathways. Suppression of RSK1 and PKA results in a decrease in phosphorylation of their respective downstream targets, Bad(Ser-112) and Bad(Ser-155). Decrease in Bad(Ser-112, Ser-155) phosphorylation results in increased binding of Bad to mitochondrial Bcl2 with concomitant displacement of Bax, followed by PTP gating induced by free mitochondrial Bax. Low conductance PTP gating by LCFA/MEDICA may account for their thyromimetic calorigenic activity in vivo.
Samovski
Dmitri
D
Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem 91120, Israel.
Kalderon
Bella
B
Yehuda-Shnaidman
Einav
E
Bar-Tana
Jacob
J
D000818:Animals; D002460:Cell Line; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D051381:Rats; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
D005227:Fatty Acids; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein; D019908:Proto-Oncogene Proteins c-raf