Succinate links TCA cycle dysfunction to inflammation by activating HIF-1α signaling in acute kidney injury

Acute kidney injury (AKI) is a prevalent clinical syndrome characterized by a rapid decline in renal function and has emerged as a significant global health concern. Although ischemia-reperfusion injury (IRI) plays a critical role in AKI pathogenesis, our understanding of the underlying pathophysiological processes remains incomplete, thereby impeding the development of effective therapeutic strategies. Mitochondrial dysfunction, tricarboxylic acid (TCA) cycle metabolic disruption, and inflammatory responses are central to AKI progression; however, their mechanistic links are poorly understood. In this study, we demonstrated that IRI significantly reduces the TCA cycle enzyme succinate dehydrogenase B (SDHB), leading to succinate accumulation in kidneys. SDHB overexpression markedly ameliorates mitochondrial damage and inflammation in tubular epithelial cells (TECs) both in vivo and in vitro. Mechanistically, succinate directly interacts with prolyl hydroxylase domain-containing protein 2 (PHD2) at the tyrosine-329 (TYR-329) site, inhibiting its activity, thereby hyperactivating the hypoxia-inducible factor-1α (HIF-1α) signaling pathway and exacerbating immune-inflammatory responses in AKI. These findings provide mechanistic insights into how TCA cycle disruptions and HIF-1α interactions drive renal inflammation, suggesting SDHB as a potential therapeutic target for AKI.