Interaction of free fatty acids with mitochondria: Coupling, uncoupling and permeability transition

Abstract

Long chain free fatty acids (FFA) exert, according to their actual concentration, different effects on the energy conserving system of mitochondria. Sub-micromolar concentrations of arachidonic acid (AA) rescue DeltapH-dependent depression of the proton pumping activity of the bc1 complex. This effect appears to be due to a direct interaction of AA with the proton-input mouth of the pump. At micromolar concentrations FFA increase the proton conductance of the inner membrane acting as protonophores. FFA can act as natural uncouplers, causing a mild uncoupling, which prevents reactive oxygen species production in the respiratory resting state. When Ca(2+)-loaded mitochondria are exposed to micromolar concentrations of FFA, the permeability of the inner membrane increases, resulting in matrix swelling, rupture of the outer membrane and release of intermembrane pro-apoptotic proteins. The characteristics of AA-induced swelling appear markedly different in mitochondria isolated from heart or liver. While in the latter it presents the canonical features of the classical permeability transition (PT), in heart mitochondria substantial differences are observed concerning CsA sensitivity, DeltaPsi dependence, reversibility by BSA and specificity for the activating divalent cation. In heart mitochondria, the AA-dependent increase of the inner membrane permeability is affected by ANT ligands such as adenine nucleotides and atractyloside. AA apparently causes a Ca2+-mediated conversion of ANT from a translocator to a channel system. Upon diamide treatment of heart mitochondria, the Ca2+/AA-induced CsA insensitive channel is converted into the classical PT pore. The relevance of these observations in terms of tissue-specific components of the putative PTP and heart ischemic and post-ischemic process is discussed.

High-sucrose diet increases ROS generation, FFA accumulation, UCP2 level, and proton leak in liver mitochondria

“…SFR mitochondria exhibited increased ROS generation despite simultaneously overexpressing UCP2. Although the function of UCP2 is still unclear, it has been linked to the accumulation of FFAs in hepatocytes and muscle cells (12,46) and to mitochondrial ROS production (43). The mild uncoupling mediated by UCP2 may accelerate respiration rates and reduce the generation of ROS.…”

Dimebon (Latrepirdine) Enhances Mitochondrial Function and Protects Neuronal Cells from Death

“…One possible mechanism is that Dimebon may act as an anti-uncoupling agent decreasing proton leakage over the inner membrane, resulting in enhanced ∆Ψm and ATP production. An example of a known anti-uncoupling agent is albumin, which binds natural uncouplers like free fatty acids [48]. In a study by Ward and colleagues, it was shown that hyperpolarization of ∆Ψm is associated with increased glucose uptake, NADPH availability, ATP levels, and survival responses during excitotoxic injury.…”

Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

“…Lipotoxic effects of free fatty acids have been suggested to be a key factor in development and also progression of hepatic steatosis (de Almeida et al, 2002;Malhi et al, 2006). In general, the term lipotoxic effects summarizes a potpourri of alterations in cellular metabolism observed in vitro upon addition of free fatty acids to cell cultures and includes 1) activation of stress-related signaling of JNK, 2) elevated expression of proinflammatory cytokines, 3) inhibition of mitochondrial ␤-oxidation, 4) elevated production of ROS, as well as enhanced generation of 5) toxic lipid intermediates and 6) lipid derivatives involved in altered cell signaling (Shimabukuro et al, 1998;Reddy, 2001;Borradaile et al, 2006b;Di Paola and Lorusso, 2006;Malhi et al, 2006). Saturated FA (i.e., palmitate) are the primary and most potent elicitors of lipotoxic effects (Eitel et al, 2002;Maedler et al, 2003;Weigert et al, 2004).…”