Accumulation of Succinate in Cardiac Ischemia Primarily Occurs via Canonical Krebs Cycle Activity

Abstract

SUMMARY Succinate accumulates during ischemia, and its oxidation at reperfusion drives injury. The mechanism of ischemic succinate accumulation is controversial and is proposed to involve reversal of mitochondrial complex II. Herein, using stable-isotope-resolved metabolomics, we demonstrate that complex II reversal is possible in hypoxic mitochondria but is not the primary succinate source in hypoxic cardiomyocytes or ischemic hearts. Rather, in these intact systems succinate primarily originates from canonical Krebs cycle activity, partly supported by aminotransferase anaplerosis and glycolysis from glycogen. Augmentation of canonical Krebs cycle activity with dimethyl-α-ketoglutarate both increases ischemic succinate accumulation and drives substrate-level phosphorylation by succinyl-CoA synthetase, improving ischemic energetics. Although two-thirds of ischemic succinate accumulation is extracellular, the remaining one-third is metabolized during early reperfusion, wherein acute complex II inhibition is protective. These results highlight a bifunctional role for succinate: its complex-II-independent accumulation being beneficial in ischemia and its complex-II-dependent oxidation being detrimental at reperfusion.

Succinate induces skeletal muscle fiber remodeling via SUCNR1 signaling

“…Regular exercise and chronic hypoxia are natural stimuli that produce sustainable cardioprotection against ischemia reperfusion . Consistent with the important role of succinate in muscle metabolism and fiber remodeling we showed, succinate is elevated in the blood in response to exercise and accumulated rapidly in hypoxic/ischemic tissues , suggesting a potential role of succinate in exercise/hypoxia‐mediated cardioprotection. Succinate may act as a paracrine or endocrine signaling molecules via SUCNR1 to regulate local cellular metabolism , or increase tissue blood supply through the renin‐angiotensin system, thereby alleviating tissue hypoxia and hypoxia adaptation of metabolism in the environment .…”

“…Succinate may act as a paracrine or endocrine signaling molecules via SUCNR1 to regulate local cellular metabolism , or increase tissue blood supply through the renin‐angiotensin system, thereby alleviating tissue hypoxia and hypoxia adaptation of metabolism in the environment . Consistently, augmentation of succinate has been shown to improve cardiac ischemic energetics, a source of damage at reperfusion . Therefore, succinic acid may not only play an important role in autocrine regulation of skeletal muscle metabolism and fiber‐type conversion, but also improve the adaptability of cardiovascular and brain tissues to the ischemic environment.…”

Succinate can shuttle reducing power from the hypoxic retina to the O2-rich pigment epithelium

“…We next tested whether malate exported by eyecups can influence retinal metabolism. Retinas in an eye are in a hypoxic environment, and hypoxic tissues can produce succinate by both canonical oxidative TCA cycle activity as well as through reverse electron transport at SDH (Chouchani et al, 2014;Zhang et al, 2018). Since retinas export succinate ( Fig.…”

“…It has been estimated that reverse SDH activity produces only about ~6% of succinate during ischemia in heart (Zhang et al, 2018). To determine if reverse SDH activity produces a more substantial amount of succinate in retina, we next quantified the contributions of reverse SDH activity and canonical TCA cycle activity to maintaining the retinal succinate pool.…”

“…Succinate accumulates in muscle, heart, kidney, liver, brain and blood during hypoxia (Cascarano et al, 1976;Chouchani et al, 2014;Hochachka et al, 1975). However, the degree to which the reverse SDH reaction contributes to succinate produced during hypoxia is debated, and the role of succinate in tissues that are in chronically hypoxic niches is largely unexplored (Chinopoulos, 2019;Chouchani et al, 2014;Zhang et al, 2018).…”