Hypoxia exposure fine-tunes mitochondrial function in sea turtle cells

Sea turtles experience extreme fluctuations in oxygen availability derived from extended breath-hold diving, yet the cellular adjustments that underlie hypoxia tolerance in these animals remain poorly understood. Here, we used metabolite profiling, extracellular flux assays, and microscopic analyses of the mitochondrial reticulum to study how primary cells derived from sea turtles and lizards cope with extended hypoxia exposure. Cells from both species proliferate in primary culture, stain positive for fibroblast markers, are metabolically active, and stabilize HIF1- when exposed to chemical or environmental hypoxia. In contrast to lizard cells, sea turtle cells exhibit a faster and more robust response to 1 or 24-hour hypoxia exposure (0.1% O2), upregulating antioxidant pathways and optimizing oxygen use rather than relying on glycolytic metabolism. Similarly, the mitochondrial reticulum is maintained without apparent fragmentation during hypoxia exposure in sea turtle cells. Consistent with these observations, mitochondrial function readily recovers in sea turtle but not lizard cells upon reoxygenation. These findings show that sea turtle cells undergo intrinsic metabolic adjustments to cope with extreme oxygen fluctuations, aligning with the remarkable hypoxic tolerance exhibited by these animals, which can endure up to 7 hours of breath-holding underwater.