Structure‐Function Relations between Fatty Acid Oxidation and the Mitochondrial Inner‐Membrane — Matrix Region

Abstract

Decreasing the osmolarity of the incubation media for rat liver mitochondria, by lowering the KCl or sucrose content, greatly increased the oxidation of palmitate, palmitoyl-CoA, palmitoyl-(-)-carnitine, octanoate and butyrate, but only slightly affected the oxidation of succinate, glutamate plus malate, and 3-hydroxybutyrate. Kinetic studies indicated that the increased rate of fatty acid oxidation commenced at the onset of incubation in the hypotonic media and remained relatively constant. This was accompanied by an increase in the 3-hydroxybutyrate: acetoacetate ratio, a higher rate of oxygen consumption, an increase in the extramitochondrial adenine-nucleotide phosphorylation-state ratio, and a greater state of reduction of the respiratory chain cytochromes b, c, and oxidase. Incubation of mitochondria in the hypotonic media caused a rapid decrease in the intermembrane and intracrystal spaces and concurrent expansion of the matrix, without changing the volume of the mitochondria. These observations indicate that expansion of the inner-membrane-matrix compartment of mitochondria in vitro specifically activates fatty acid oxidation at the site of beta-oxidation or at the site of its interaction with the respiratory chain, with a consequent increase in the states of reduction and phosphorylation of the mitochondria. Evidence is also presented which suggests that the activation of mitochondrial fatty acid oxidation by Ca2+ is initiated by a Ca2+-induced alteration of the structure or volume of the inner-membrane-matrix region.

Redox control of β‐oxidation in rat liver mitochondria

“…Such an effect could be mediated by NAD+/NADH pool turnover, so that a dual inhibition of both the NAD' and ETF-linked stages by hyperosmotic conditions would explain the pattern of intermediates detected, with the ETF-linked stage inhibited more than the NAD+-linked stage at high osmolalities. However, the data of Otto and Ontko (1982) are not in agreement with this hypothesis as they found that 3-hydroxybutyrate/acetoacetate ratios increased with decreasing osmolality, rather than remaining constant, as would be expected if the NAD+/ NADH ratios were constant. Sub-compartmentation of intramitochondrial NAD' (Sumegi and Srere, 1984;Fukushima et al, 1989) could explain this discrepancy.…”

“…This steady 30% reduction and the subsequent turnover of the NAD'NADH pool via the activity of complex I is probably important for the control of P-oxidation under these conditions. (Osmundsen and Bremer, 1976), by the rates of ketogenesis (Otto and Ontko, 1982), and polarographically with hexadecanoyl-carnitine by Halestrap and Dunlop (1986).…”

“…There is however a more marked effect of osmolality on p-oxidation flux (Osmundsen and Bremer, 1976;Otto and Ontko, 1982;Halestrap and Dunlop, 1986) and a locus between ETF and the coenzyme Q pool has been proposed as the site of this control (Halestrap and Dunlop, 1986). Such control may be important physiologically, for example in the hormonal control of Boxidation by glucagon (Halestrap, 1989;Tosh et al, 1988).…”

Spontaneously Immortalized Mouse Embryo Fibroblasts: Growth Behavior of Wild-Type and Vimentin-Deficient Cells in Relation to Mitochondrial Structure and Activity

“…On the assumption that the cloned, immortalized vim Ϫ fibroblasts are restricted in their metabolic capacities partially because of a slow turnover of mtDNA-encoded mitochondrial proteins, efficient usage of already existent mitochondrial metabolons should be a remedial measure for solving this problem. This might include, on the one hand, swelling of the inner membrane-matrix compartment, a process which, via anchorage of multienzyme complexes of ␤-oxidation to the inner membrane (Parker and Engel, 2000), specifically activates fatty acid oxidation with concomitant elevation of the mitochondrial energy state (Otto and Ontko, 1982). Fatty acids are not only excellent respiratory substrates feeding electrons into the mitochondrial energy-generating respiratory chain, but they also promote mitochondrial swelling (Schönfeld et al, 2000).…”

Energetics of swelling in isolated hepatocytes: A comprehensive study

“…For instance, in the presence of glucagon, mitochondrial respiratory rate, pyruvate metabolism and citrulline synthesis are stimulated [18]. When external osmolarity was decreased, fatty acid oxidation was stimulated while cytochromes were more reduced [19]. In conditions of matrix volume condensation, an inhibition of mitochondrial substrate oxidation has been observed and interpreted as a consequence of an osmotically sensitive diffusion of quinones through the mitochondrial membrane [20].…”