[Age-related Peculiarities of Succinate Effect on Induced Lipid Peroxidation in Rat Liver Mitochondria].

The antioxidant effect of succinate and 3-hydroxybutyrate oxidation on the kinetics of lipid peroxidation induced by ATP-Fe2+ complex in isolated rat liver mitochondria of old (1.0-1.5 years) and young (3 months) male rats was investigated. The rate of induced lipid peroxidation V(LPO) in rat liver mitochondria and the half-time of oxygen consumption Δt50, which included the lag period and the initiation. phase, was recorded polarographically. Without exogenous oxidative-substrates V(LPO) was slightly higher in mitochondria of old animals, but the onset of lipid peroxidation cascade was significantly earlier than in young animals. Incubation of mitochondria with 5mM succinate for 1 min inhibited V(LPO) by 15% in young animals and by 35% in old animals. However, only in mitochondria of old animals Δt50 increased by 19% as compared to lipid peroxidation without substrates. V(LPO) in mitochondria of young animals did not significantly change during 3-hydroxybutyrate oxidation, while in mitochondria of old animals it was reduced by 19% with a slight increase in Δt50. To simulate age-dependent dysfunction we damaged isolated mitochondria by a series of freeze-thaw cycles, which caused a significant increase of V(LPO) of.both age groups. Succinate oxidation inhibited V(LPO) in damaged mitochondria in all cases by 56%, as compared to V(LPO) without oxidative substrates and extended At50 twofold in mitochondria of young animals. Oxidation of 3-hydroxybutyrate had no effect on V(LPO) in damaged mitochondria regardless of animal, age and extended Δt50 by 48% in mitochondria of young animals. Thus, the antioxidant effect of succinate oxidation can prevent lipid peroxidation damage and may exhibit geroprotective action at the level of aging mitochondria. Therefore, the antioxidant effect is due to the process of substrate oxidation in the respiratory chain but not because of an interaction of their structures with membrane lipids per se.

Burst of succinate dehydrogenase and α-ketoglutarate dehydrogenase activity in concert with the expression of genes coding for respiratory chain proteins underlies short-term beneficial physiological stress in mitochondria.

Conditions for the realization in rats of moderate physiological stress (PHS) (30-120 min) were selected, which preferentially increase adaptive restorative processes without adverse responses typical of harmful stress (HST). The succinate dehydrogenase (SDH) and α-ketoglutarate dehydrogenase (KDH) activity and the formation of reactive oxygen species (ROS) in mitochondria were measured in lymphocytes by the cytobiochemical method, which detects the regulation of mitochondria in the organism with high sensitivity. These mitochondrial markers undergo an initial 10-20-fold burst of activity followed by a decrease to a level exceeding the quiescent state 2-3-fold by 120 min of PHS. By 30-60 min, the rise in SDH activity was greater than in KDH activity, while the activity of KDH prevailed over that of SDH by 120 min. The attenuation of SDH hyperactivity during PHS occurs by a mechanism other than oxaloacetate inhibition developed under HST. The dynamics of SDH and KDH activity corresponds to the known physiological replacement of adrenergic regulation by cholinergic during PHS, which is confirmed here by mitochondrial markers because their activity reflects these two types of nerve regulation, respectively. The domination of cholinergic regulation provides the overrestoration of expenditures for activity. In essence, this phenomenon corresponds to the training of the organism. It was first revealed in mitochondria after a single short-time stress episode. The burst of ROS formation was congruous with changes in SDH and KDH activity, as well as in ucp2 and cox3 expression, while the activity of SDH was inversely dependent on the expression of the gene of its catalytic subunit in the spleen. As the SDH activity enhanced, the expression of the succinate receptor decreased with subsequent dramatic rise when the activity was becoming lower. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaption and therapy.