Mitochondrial disease in mouse results in increased oxidative stress

Abstract

It has been hypothesized that a major factor in the progression of mitochondrial disease resulting from defects in oxidative phosphorylation (OXPHOS) is the stimulation of the mitochondrial production of reactive oxygen species (ROS) and the resulting damage to the mtDNA. To test this hypothesis, we examined the mitochondria from mice lacking the heart͞muscle isoform of the adenine nucleotide translocator (Ant1), designated Ant1 tm2Mgr (؊͞؊) mice. The absence of Ant1 blocks the exchange of ADP and ATP across the mitochondrial inner membrane, thus inhibiting OXPHOS. Consistent with Ant1 expression, mitochondria isolated from skeletal muscle, heart, and brain of the Ant1-deficient mice produced markedly increased amounts of the ROS hydrogen peroxide, whereas liver mitochondria, which express a different Ant isoform, produced normally low levels of hydrogen peroxide. The increased production of ROS by the skeletal muscle and heart was associated with a dramatic increase in the ROS detoxification enzyme manganese superoxide dismutase (Sod2, also known as MnSod) in muscle tissue and muscle mitochondria, a modest increase in Sod2 in heart tissue, and no increase in heart mitochondria. The level of glutathione peroxidase-1 (Gpx1), a second ROS detoxifying enzyme, was increased moderately in the mitochondria of both tissues. Consistent with the lower antioxidant defenses in heart, the heart mtDNAs of the Ant1-deficient mice showed a striking increase in the accumulation of mtDNA rearrangements, whereas skeletal muscle, with higher antioxidant defenses, had fewer mtDNA rearrangements. Hence, inhibition of OXPHOS does increase mitochondrial ROS production, eliciting antioxidant defenses. If the antioxidant defenses are insufficient to detoxify the ROS, then an increased mtDNA mutation rate can result.

Mitochondrial ATP transporter Ant2 depletion impairs erythropoiesis and B lymphopoiesis

“…Consistent with decreases in respiratory capacity, cellular ATP levels were lower in Ant2-depleted splenocytes (Figure 7d), suggesting that increased glycolysis is not sufficient for compensation. In contrast to the previous report of effects of Ant1 depletion in heart and skeletal muscle, 23 the mitochondrial deoxyribonucleic acid (mtDNA) copy numbers in Ant2 SIBN/Y spleens were rather reduced (Figure 7e), and we did not see an increase in mitochondrial number either at electron microscopic analysis of the spleen (Figure 7f). These data indicate there was no obvious compensatory mitochondrial proliferation in the Ant2-depleted spleens.…”

Sequential changes in superoxide production, anion carriers and substrate oxidation in skeletal muscle mitochondria of heat‐stressed chickens

“…In fact, Echtay et al [28] also demonstrated that the uncoupling action of ANT as well as UCP was stimulated by 4-hydroxynonenal (HNE). It was also shown that knocking out one of two ANT isoenzymes (muscle-specific ANT1) results in a strong increase in ROS production by muscle mitochondria [29]. Therefore, we studied the possible roles of avANT in suppressing superoxide production via an uncoupling action in heat-stressed chickens, but found that the duration of heat stress did not affect avANT transcript expression (Fig.…”

L‐carnitine inhibits hepatocarcinogenesis via protection of mitochondria

“…Thus, mitochondrial DNA harboring certain mutations elicited from free radicals might generate abnormal RNAs or proteins in the electron transport system, the latter of which may promote the leakage of electrons from the mitochondrial electron transport chain. 38,39 It has also been well documented that oxidative stress enhances lipid peroxidation and degradation of phospholipids, thereby increasing free forms of fatty acids. 40,41 Because free-form long-chain fatty acids are hydrophobic anions that exhibit properties similar to those of anionic detergents, a rapid increase in their tissue levels might disturb the structure and functions of mitochondrial membranes, the integrity of which is essential to normally functioning mitochondria, 22,42 and the destruction of which would also lead to the leakage of electrons from the mitochondrial electron transport chain.…”

“…40,41 Because free-form long-chain fatty acids are hydrophobic anions that exhibit properties similar to those of anionic detergents, a rapid increase in their tissue levels might disturb the structure and functions of mitochondrial membranes, the integrity of which is essential to normally functioning mitochondria, 22,42 and the destruction of which would also lead to the leakage of electrons from the mitochondrial electron transport chain. 38,39 Thus, mitochondria might be an important target for copper-induced toxicity and play an important role in the pathogenesis of LEC rats. In fact, several investigations have revealed that there are striking ultrastructural and functional abnormal alterations in the mitochondria of hepatocytes in LEC rats.…”