Endogenous Protective Mechanisms in Remodeling of Rat Heart Mitochondrial Membranes in the Acute Phase of Streptozotocin-Induced Diabetes

Abstract

The aim of present study was to investigate functional and physical alterations in membranes of heart mitochondria that are associated with remodeling of these organelles in acute phase of streptozotocin-induced diabetes and to elucidate the role of these changes in adaptation of the heart to acute streptozotocin-induced diabetes (evaluated 8 days after single dose streptozotocin application to male Wistar rats). Action of free radicals on the respiratory chain of diabetic-heart mitochondria was manifested by 17 % increase (p<0.05) in oxidized form of the coenzyme Q(10) and resulted in a decrease of states S3 and S4 respiration, the respiratory control index, rate of phosphorylation (all p<0.01) and the mitochondrial transmembrane potential (p<0.05), but the ADP/O ratio decreased only moderately (p>0.05). On the contrary, membrane fluidity and the total mitochondrial Mg2+-ATPase activity increased (both p<0.05). In diabetic heart mitochondria, linear regression analysis revealed a reciprocal relationship between the increase in membrane fluidity and decrease in trans-membrane potential (p<0.05, r = 0.67). Changes in membrane fluidity, transmembrane potential, Mg2+-ATPase activity and the almost preserved ADP/O ratio appear as the manifestation of endogenous protective mechanisms participating in the functional remodeling of mitochondria which contributes to adaptation of the heart to diabetes.

Dichloroacetate as a metabolic modulator of heart mitochondrial proteome under conditions of reduced oxygen utilization

“…Some authors do not support the concept of pseudohypoxia because they did not observe changes in the amounts of NADH and NAD +13 . Our results from previously published work demonstrated mitochondrial respiratory chain damage of the diabetic myocardium but without disconnection oxidation from oxidative phosphorylation and slowed-down electron flow associated with a reduction in the rate of oxidative phosphorylation during oxidation of succinate as well as glutamate as substrates 6 . DM-induced impairment of electron transport in the respiratory chain is likely to be more pronounced in substrates whose oxidation occurs through a change in the NADH/NAD + ratio.…”

“…The state of reduced oxygen utilization, which develops in the myocardium in the conditions of acute experimental streptozotocin-induced diabetes mellitus (DM), can be associated with the triggering of adaptive processes leading to paradoxically lower susceptibility to ischemia in experimental studies [1][2][3][4] . Activation of endogenous protective pathways lead to a positive remodeling of the mitochondrial membrane, acting against the increased energy demand associated with DM itself [5][6][7][8] . It has been proposed that DM shares some molecular pathways with ischemic preconditioning (PC) and with other forms of endogenous protection against ischemia/reperfusion (I/R) injury 1,2,9 .…”

“…The lack of oxygen in DM is not caused by its absence but rather by a disruption of the respiratory chain of cardiac mitochondria, which impairs its ability to utilize it 9,10 . From a pathophysiological point of view, this state may be termed pseudohypoxia, a situation that resembles mild hypoxia, but with a considerable decrease in tissue pO 2 and the accompanying switch over to lactate production being absent 6,11 . Hyperglycemia is often associated with pseudohypoxia, which is characterized by an increase in the ratio of nicotinamide adenine dinucleotide (NADH/NAD + ) 12,13 .…”

“…In connection with the compromised energy supply in hypoxic conditions of the acute phase of diabetic myocardial disease 20 , endogenous protective mechanisms associated with functional mitochondrial remodeling are activated at the level of chemical and physical properties of mitochondrial membranes 6,11 .…”

Dichloroacetate and reduced oxygen utilization induced metabolic regulation of the heart: A focus on the cardiac mitochondrial proteome

“…It has provided a signi cant contribution to the issue of promoting the survival of diabetic myocardium. Previous studies have shown that the pseudohypoxic state of the myocardium is accompanied by increased ROS production 50,51 . The unexpected nding of increased cardiac mitochondrial uidity in rats with D, despite the increase in ROS production assumed to be linked to membrane rigidization rather than uidization, points to the ROS signaling role 52 .…”