Succinate and lactate produced as conserved biomarkers through chronic and transient substrate-level phosphorylation: from microorganisms to cancer.

ATP is the primary energy currency required by living organisms. Mitochondrial oxidative phosphorylation (OxPhos) produces most of the ATP in quiescent and differentiated cells. OxPhos interruption results in analogous bioenergetic adaptations across divergent evolutionary taxa, yet this adaptation is poorly recognized. Oxygen availability is a major determinant of the source of ATP generation across most eukaryotic cell types. Acute oxygen deprivation, mitochondrial dysfunction, high energy demand, or other metabolic cues can shift relative ATP production from OxPhos to high-throughput fermentation via substrate-level phosphorylations (SLPs). Glucose-derived lactate and glutamine-derived succinate are biomarkers of cytosolic and mitochondrial SLP, respectively. The extracellular accumulation of these metabolites is observed in a broad range of biological systems, including unicellular bacteria and yeast to more complex mammalian cells, including those of the immune system, retina, and muscle. Unsurprisingly, many cancer cells accumulate excess lactate and succinate due to chronic OxPhos insufficiency. This review links ostensibly unique cases of metabolic disruption to the accumulation of lactate and succinate as biomarkers of compensatory fermentative metabolism through cytosolic and mitochondrial SLP. Fundamental principles of cellular energy and environmental adaptation are reviewed that span a broad range of biological complexity.