Aglycemia triggers alternative electron transport to sustain mesenchymal stem cell survival under anoxia.

Adult stem cells, including mesenchymal stem cells (MSC), display marked metabolic flexibility, functioning across anaerobic to microaerophilic conditions. While their survival under energy-restrictive environments is known, the underlying metabolic mechanisms remain incompletely defined. Here, combining functional assays, omics, and multiparametric energetic profiling, we elucidate the adaptations that enable MSC, unlike differentiated cells, to endure prolonged anoxia or anoxia/aglycemia (ischemia-like) conditions. We show that MSC proliferation under anoxia and normal glycemia depends mainly on lactate fermentation, whereas survival under combined anoxia and aglycemia relies on a specific mitochondrial reprogramming. Notably, anaerobic mitochondrial activity including Krebs cycle turnover and sulfide oxidation can proceed through a canonical electron transport chain using an alternative electron acceptor. This anaerobiosis-stemness link positions stem cells as living molecular fossils, preserving features of primordial eukaryotic bioenergetics and illuminating the evolutionary depth of mitochondrial plasticity.