Abstract
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.
Highlights
Mitochondrial inner membrane in their protonated form followed by efflux of the fatty acid anion through anion channels (Ref. 1; reviewed in Ref. 2)
In line with permeability transition pore (PTP) gating by long chain fatty acids (LCFA), MEDICA analogs were found to induce Caϩ2-dependent, cyclosporin A (CsA)-sensitive decrease in mitochondrial membrane potential in isolated mitochondria, implying PTP gating by MEDICA analogs in vitro [22]
The protonophoric and PTP gating activity of LCFA has previously been extensively verified in isolated mitochondria
Summary
Mitochondrial inner membrane in their protonated form followed by efflux of the fatty acid anion through anion channels (Ref. 1; reviewed in Ref. 2). Increased oxygen consumption induced by fatty acids in the perfused liver or in isolated liver cells has been reported to be essentially or partly eliminated upon blocking oxidative phosphorylation by added oligomycin or atractyloside, refuting classic mitochondrial uncoupling [12,13,14,15]. Inner mitochondrial membrane potential measured in isolated hepatocytes, or phosphorylation potential measured in situ in the perfused heart were found to be unaffected or rather increased by added fatty acids. Treatment of lean rats with MEDICA analogs results in pronounced increase in oxygen consumption accompanied by decrease in liver mitochondrial phosphate potential and cytosolic redox potential, reflecting mitochondrial uncoupling in vivo [18]. Treatment of obese leptin receptor-deficient rats (e.g. Zucker, cp/cp) with MEDICA analogs results in increase in oxygen consumption and food consumption with concomitant decrease in weight gain, implying increased total body energy expenditure [19, 20]
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