Acid enhancement of ROS generation by complex-I reverse electron transport is balanced by acid inhibition of complex-II: Relevance for tissue reperfusion injury

Abstract

Generation of mitochondrial reactive oxygen species (ROS) is an important process in triggering cellular necrosis and tissue infarction during ischemia-reperfusion (IR) injury. Ischemia results in accumulation of the metabolite succinate. Rapid oxidation of this succinate by mitochondrial complex II (Cx-II) during reperfusion reduces the co-enzyme Q (Co-Q) pool, thereby driving electrons backward into complex-I (Cx-I), a process known as reverse electron transport (RET), which is thought to be a major source of ROS. During ischemia, enhanced glycolysis results in an acidic cellular pH at the onset of reperfusion. While the process of RsET within Cx-I is known to be enhanced by a high mitochondrial trans-membrane ΔpH, the impact of pH itself on the integrated process of Cx-II to Cx-I RET has not been fully studied. Using isolated mouse heart and liver mitochondria under conditions which mimic the onset of reperfusion (i.e., high [ADP]), we show that mitochondrial respiration (state 2 and state 3) as well as isolated Cx-II activity are impaired at acidic pH, whereas the overall generation of ROS by Cx-II to Cx-I RET was insensitive to pH. Together these data indicate that the acceleration of Cx-I RET ROS by ΔpH appears to be cancelled out by the impact of pH on the source of electrons, i.e. Cx-II. Implications for the role of Cx-II to Cx-I RET derived ROS in IR injury are discussed.

Baicalein resensitizes tamoxifen‐resistant breast cancer cells by reducing aerobic glycolysis and reversing mitochondrial dysfunction via inhibition of hypoxia‐inducible factor‐1α

“…Furthermore, mitochondria are important sources of ROS generation, and accumulation of high ROS levels induces cell apoptosis. 58 As baicalein treatment upregulated the mitochondrial number, OHT in combination with baicalein resulted in significant mitochondria‐associated ROS generation and exacerbated intracellular ROS accumulation, causing loss of MMP and leading to apoptosis in TAM‐resistant cells. Importantly, the active oxygen scavenger NAC reversed the pro‐apoptotic effect of combined baicalein and TAM treatment of TAM‐resistant cells, implying that ROS are the critical mediator involved in this apoptotic effect.…”

The Role of Metabolism in Heart Failure and Regeneration

“…These results demonstrate that SDH inhibition during I/R injury blocks the SDH-mediated succinate accumulation, thus protecting the heart against the redox insult during I/R injury. Interestingly, a recent study demonstrated that succinate accumulation in ischemia/reperfusion is not due to the reverse activity of SDH, but rather due to canonical TCA cycle activity (108). Thus, although succinate accumulation during ischemia is conserved across vertebrates, the proposed mechanism of succinate accumulation remains to be further understood.…”

Reactive oxygen species-based nanomaterials for the treatment of myocardial ischemia reperfusion injuries

“…In addition, the generation of O 2 · − can also be caused by reverse electron transport (RET) in complex I when the pool of CoQ becomes over-reduced with electrons from complex II. In RET process, electrons first enter complex II through succinate oxidation and reach CoQ, and then are directed back to complex I instead of proceeding forward to complex III [ 47 , 82 , 94 ]. Succinates from ischemic accumulation are rapidly re-oxidized by the succinate dehydrogenase of complex II, which transfers electrons from complex II to complex I, and produces O 2 ·− [ 90 , 95 ].…”