Interplay between ischemia–reperfusion and metabolic reprogramming

Abstract

A common pathological process associated with acute organ injury, which is closely connected to metabolic reprogramming, is ischemia–reperfusion injury (IRI). Ischemia leads to decreased oxygen and substrate availability, with rapid activation of energy-sensing pathways, increased dependence on glycolysis, and predisposition of mitochondria to later oxidative injury. Reperfusion involves the rapid restoration of blood supply, with oxidative stress, inflammatory responses and remodeling of metabolic networks. Here, we summarize current evidence for the bidirectional interaction between IRI and metabolic reprogramming by organizing conceptual topics around glucose metabolism, lipid remodeling, amino acid metabolism and tricarboxylic acid cycle (TCA)-centered substrate convergence. Here, we focus on metabolic events according to the ischemic and reperfusion stages, from the early to the delayed phase, including succinate accumulation, reactive oxygen species (ROS) generation via reverse electron transport, mitochondrial quality control, immunometabolic remodeling, as well as apoptosis, ferroptosis, pyroptosis and post-translational modifications. In addition, recent advances in metabolic biomarkers, experimental models and novel therapeutic strategies are highlighted. Recent evidence suggests that metabolic reprogramming is not simply a passive response to IRI, but an active regulatory process that controls the initiation and amplification of injury, as well as its resolution. A metabolomic framework within a time-staged and cell death-centered context may inform more clinically useful biomarkers and intervention windows for IRI.