Mitochondrial Regulation of Brown Adipose Tissue During Hypoxia in Rodents.

Brown adipose tissue (BAT) is a mitochondria-rich thermogenic organ that supports nonshivering thermogenesis through uncoupling protein 1-mediated proton leak. Because this process requires exceptionally high rates of oxidative metabolism, BAT function is critically dependent on oxygen availability. Environmental hypoxia therefore imposes a major energetic challenge, forcing organisms to balance thermogenic heat production against preservation of oxygen and adenosine triphosphate for essential cellular functions. This mini-review examines how BAT mitochondria respond to hypoxia in hypoxia-intolerant laboratory rodents vs hypoxia-tolerant social African mole rats, with a particular focus on mitochondrial regulation, reversibility of suppression, and implications for metabolic disease. In laboratory rodents, BAT suppression is largely constraint driven and associated with hypoxia-inducible factor-dependent transcriptional reprogramming, impaired β-adrenergic signaling, reduced uncoupling protein 1 expression, altered lipid metabolism, mitochondrial fragmentation, diminished oxidative phosphorylation, and increased reactive oxygen species production. These changes are often maladaptive and accompanied by persistent mitochondrial dysfunction. In contrast, social African mole rats exhibit coordinated and reversible metabolic suppression in which BAT thermogenesis is actively downregulated to match reduced oxygen availability. This adaptive response preserves mitochondrial integrity through controlled reductions in oxidative phosphorylation, reversible suppression of uncoupling protein 1, regulated mitochondrial fission, and avoidance of excessive mitophagy or oxidative damage. These divergent strategies provide a valuable comparative framework for understanding mitochondrial control of energy expenditure in hypoxia. Importantly, many mechanisms observed in hypoxia-intolerant BAT parallel mitochondrial dysfunction in obesity and type 2 diabetes, highlighting BAT mitochondria as potential therapeutic targets for metabolic disease and hypoxic injury.