Mitochondrial Regulation of Brown Adipose Tissue During Hypoxia in Rodents

Abstract

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.

INTRODUCTION: MITOCHONDRIA ARE CENTRAL TO NONSHIVERING THERMOGENESIS

Brown adipose tissue (BAT) is a specialized thermogenic organ that enables mammals to defend body temperature through nonshivering thermogenesis (NST), a process fundamentally dependent on mitochondrial bioenergetics.^1,2 Unlike white adipose tissue, which primarily functions in energy storage, BAT is densely packed with mitochondria and highly vascularized, reflecting its role as a major site of aerobic energy expenditure.^1,2 In canonical oxidative phosphorylation, electrons derived from NADH and FADH₂ are transferred through electron transport system complexes I through IV, driving proton pumping across the inner mitochondrial membrane and establishing a proton gradient. This gradient is then used by adenosine triphosphate (ATP) synthase (complex V) to phosphorylate adenosine diphosphate. In BAT, however, uncoupling protein 1 (UCP1) provides an alternative pathway for proton reentry into the mitochondrial matrix, effectively short-circuiting ATP production and converting potential energy into heat.^3,4 This process dramatically increases substrate oxidation rates because mitochondria must accelerate electron transport to maintain the proton gradient in the presence of UCP1-mediated leak, thereby increasing oxygen consumption. As a result, activated BAT exhibits some of the highest mass-specific metabolic rates observed in mammalian tissues.⁵ For example, cold exposure can increase whole-body oxygen consumption severalfold in small mammals, with BAT contributing a substantial proportion of this increase.⁶

ENERGETIC CONSIDERATIONS OF MITOCHONDRIAL THERMOGENESIS IN A HYPOXIC ENVIRONMENT

Generally, oxygen availability is a critical determinant of mitochondrial function because oxygen serves as the terminal electron acceptor in the electron transport system.⁷ Under normoxic conditions, abundant oxygen availability ensures efficient electron flow and minimizes electron leak. However, when oxygen levels decline (ie, in hypoxia), electron transport becomes constrained, leading to reduced proton pumping, diminished ATP synthesis, and increased likelihood of electron leak and reactive oxygen species generation.^8,9 Thus, any reduction in oxygen availability directly compromises the ability of mitochondria to sustain proton gradient formation, which limits UCP1-mediated heat production in BAT. Accordingly, the onset of hypoxia forces organisms to reprioritize energy allocation. Essential cellular processes, including maintenance of ion gradients, neuronal activity, and biosynthesis, must be preserved to ensure survival.^9–11 In contrast, thermogenesis, while beneficial, is not immediately essential in all contexts, particularly if environmental temperatures are moderate or if alternative strategies (eg, behavioral thermoregulation) are available. This creates a critical trade-off: should limited oxygen and metabolic resources be devoted to maintaining body temperature or conserved to support vital cellular functions? The answer to this question varies across species and ecological niches.

In hypoxia-intolerant rodents, such as laboratory mice and rats, the physiological response to hypoxia often involves a partial reduction in metabolic rate and suppression of BAT activity. However, this response is frequently not sufficient to match the hypoxic drop in aerobic energy production, leading to mismatches between energy supply and demand, accumulation of metabolic by-products, and increased oxidative stress.^9,12 As a result, such hypoxia-intolerant rodents may experience impaired thermoregulation, reduced physiological performance, and eventually cellular and tissue damage under hypoxic conditions. In contrast, some hypoxia-tolerant rodents have evolved strategies to resolve this trade-off more effectively. Hypoxia-tolerant social African mole rats in particular can dramatically reduce their metabolic rate by lowering body temperature and suppressing nonessential processes, including thermogenesis, in a coordinated manner, while staying conscious and active.^9,12–15 This state of metabolic suppression minimizes oxygen demand and supports survival under conditions that would be lethal to other mammals.

MOLECULAR AND MITOCHONDRIAL MECHANISMS OF BAT SUPPRESSION IN HYPOXIA-INTOLERANT LABORATORY RODENTS

Both hypoxia-tolerant and hypoxia-intolerant rodents suppress BAT activity under low oxygen conditions. However, the nature of this suppression differs profoundly (Figure 1). In hypoxia-intolerant laboratory rodents, BAT suppression is largely driven by constraints imposed by reduced oxygen availability and mediated by hypoxia-inducible factor (HIF)-dependent transcriptional changes, impaired β-adrenergic signaling, and mitochondrial dysfunction.^16–19 While these mechanisms reduce thermogenic output, they are often incomplete and accompanied by deleterious effects, including oxidative stress, structural mitochondrial damage, and impaired metabolic flexibility.^20,21 As a result, BAT function may not be fully restored upon reoxygenation, leading to persistent deficits in thermogenic capacity.

Figure 1. Major Effects of Environmental Hypoxia in Laboratory Rodents. Schematic comparing the major effects of environmental hypoxia on hypoxia-tolerant African mole rats vs hypoxia-intolerant laboratory rodents.

There are several cellular mechanisms that are thought to contribute to these changes. First, HIF-1α is stabilized and coordinates a broad metabolic rewiring that alters BAT biology during hypoxia. For example, in transgenic mice with constitutive adipose-specific HIF-1α overexpression, oxygen consumption in brown adipocytes is reduced by approximately 50%, associated with lower mitochondrial content and decreased peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and UCP2 levels, demonstrating the profound impact of sustained HIF activation on BAT bioenergetics.²² In brown adipocytes, the induction of hypoxia-responsive genes also requires the peroxisome proliferator-activated receptor-γ coactivators PGC-1α and PGC-1β; knockdown of these cofactors eliminates the cellular response to low oxygen, highlighting an essential interaction between the HIF pathway and the PGC-1 transcriptional axis in BAT.²³

Beyond transcriptional regulation, brown fat cells in hypoxia-intolerant laboratory rodents become less responsive to hormonal adrenaline signals that normally trigger thermogenesis,²⁴ and other aspects of lipid metabolism are also downregulated or blunted in hypoxia. For example, the lipid droplet coat protein perilipin 5 (PLIN5), which coordinates lipid metabolism and mitochondrial function in BAT, is upregulated in hypobaric hypoxia in mice.²⁵ PLIN5 is abundantly expressed in oxidative tissues such as brown adipocytes and stabilizes lipid droplets and promotes the juxtaposition of lipid droplets and mitochondria to drive fatty acid beta oxidation. In normoxic cold environments, sustained PLIN5 upregulation boosts thermogenic gene transcription, tightens mitochondrial cristae structure, and enhances uncoupled respiration.²⁶ However, with chronic hypoxia exposure, the elevation in PLIN5 is deleterious: although lipid droplets are enlarged and lipid accumulation is greater, thermogenic responses to cold are impaired, reflecting defective lipolysis.²⁵

Hypoxia also triggers marked ultrastructural alterations of mitochondria in BAT from hypoxia-intolerant rodents. For example, mitochondrial density declines, mitochondrial networks are disrupted, and cristae become damaged, undermining the foundation of heat-producing respiration.²⁴ These sequential structural defects collectively diminish BAT oxidative capacity and thermogenic function. Taken together, BAT suppression in hypoxia-intolerant laboratory rodents is mediated by a complex interplay of molecular and mitochondrial mechanisms. Importantly, these changes are typically irreversible and are often accompanied by oxidative stress and mitochondrial dysfunction, reflecting a maladaptive response to hypoxia.

ADAPTIVE SUPPRESSION OF BAT MITOCHONDRIA IN HYPOXIA-TOLERANT AFRICAN MOLE RATS

In contrast to hypoxia-intolerant laboratory rodents, some hypoxia-tolerant rodents exhibit highly coordinated and reversible strategies to reduce metabolic demand during oxygen limitation. Reduced thermogenesis, where possible, is a key adaptive mechanism supporting this metabolic rate suppression. This process is typically coordinated with whole-animal metabolic suppression, ensuring that energy demand is precisely matched to oxygen availability.¹³ Crucially, mitochondrial integrity is typically preserved, allowing full recovery of function when oxygen levels are restored. Among such species, social African mole rats, and particularly the naked mole rat (NMR; Heterocephalus glaber) have recently emerged as powerful models for understanding how mitochondrial function, including that of BAT, is actively (and presumably beneficially) regulated under hypoxia in hypoxia-tolerant rodents and the role of mitochondria in regulating downstream metabolic suppression.^27–29 Indeed, rather than displaying mitochondrial dysfunction, NMRs and other social African mole rats engage in controlled metabolic suppression, in which BAT thermogenesis is selectively, rapidly, and reversibly inhibited as part of a broader organismal response.³⁰ Specifically, whole-body metabolic rate can decrease by up to ~85% under severe hypoxia,^31–34 allowing prolonged survival without loss of cellular integrity. Importantly, this suppression is not a passive consequence of oxygen limitation but rather an actively regulated process involving coordinated downregulation of ATP-consuming pathways.^28,35–37 This strategy includes suppression of nonessential energetic processes, including thermogenesis (see later). Given the high oxygen demand of BAT, downregulating its activity provides a substantial energetic advantage under hypoxia.

This system is best studied in heterothermic NMRs, which possess functional BAT and are capable of thermogenesis under normoxic conditions.^30,38–41 Interscapular NMR BAT depots express UCP1 and display typical features of thermogenic tissue, including high mitochondrial density, active oxidative phosphorylation, and sensitivity to adrenergic stimulation, indicating conserved thermogenic machinery (Figure 2).^30,38 However, their reliance on BAT for thermoregulation is reduced compared to small surface-dwelling mammals, primarily due to their relatively warm and thermostable subterranean environment and the extensive employment of huddling and other forms of behavioral thermogenesis in their eusocial colony groups.⁴²

Figure 2. Functional Adaptations to BAT Function in Naked Mole Rats Exposed to Hypoxia. OXPHOS indicates oxidative phosphorylation; UCP1, uncoupling protein 1.

NMR BAT thermogenesis is actively suppressed during in vivo hypoxia (7% O₂), which results in rapid cessation of BAT heat production, accompanied by a decrease in body temperature and metabolic rate.^30,41 Importantly, this response is tightly correlated with changes in mitochondrial function rather than with structural damage. At the mitochondrial level, hypoxia induces a coordinated downregulation of oxidative phosphorylation. Protein analyses reveal decreased abundance of electron transport chain complexes I through V, leading to reduced proton gradient formation and diminished respiratory capacity.³⁰ Concurrently, UCP1 protein levels are rapidly reduced, further limiting proton leak and thermogenic output. Importantly, these changes are reversible. Upon reoxygenation, BAT mitochondrial thermogenic capacity is restored, indicating that BAT mitochondria enter a regulated low-activity state rather than undergoing irreversible damage. This reversibility distinguishes adaptive suppression from the dysfunction observed in hypoxia-intolerant rodents.

Mitochondrial dynamics play a key role in regulating BAT function under hypoxia. In NMRs, hypoxia promotes mitochondrial fission, leading to smaller organelles with reduced oxidative capacity.³⁰ This shift is mediated by increased activity of fission proteins such as Drp1, which fragment mitochondrial networks and reduce bioenergetic output. Unlike in hypoxia-intolerant laboratory rodents, however, this fission does not lead to widespread mitophagy or apoptosis. Instead, markers of mitophagy are suppressed, suggesting that mitochondria are preserved in a dormant state rather than degraded. This allows for rapid reactivation upon return to normoxia. This strategy likely minimizes the energetic cost of rebuilding mitochondrial networks and preserves cellular integrity during repeated hypoxic episodes. It would also prevent the accumulation of damaged mitochondria, which could otherwise generate excessive reactive oxygen species upon reoxygenation.

While NMRs represent an extreme example of hypoxia tolerance, similar strategies are likely present in other species. For example, several other social African mole rats (but not a solitary African mole rat) exhibit reduced UCP1 expression and decreased body temperature under hypoxia.³⁰ This suggests convergent evolution of BAT suppression as an adaptive response. Conversely, high-altitude rodents, such as deer mice (Peromyscus maniculatus), also display modifications in BAT mitochondrial function and oxygen utilization. Such species often exhibit increased mitochondrial efficiency, enhanced capillary density, and altered substrate metabolism.^43,44 However, complete suppression of BAT thermogenesis is less commonly observed in such high-altitude species, reflecting differences in ecological demands in this cold environment.

PARALLELS BETWEEN ENVIRONMENTAL HYPOXIA AND METABOLIC DISEASE

Mechanistically, many of the pathways activated by hypoxia in BAT of hypoxia-intolerant laboratory rodents, including mitochondrial dysfunction characterized by reduced oxidative capacity and increased reactive oxygen species production, are also observed in human metabolic disease.^45–47 Thus, the mechanisms regulating BAT during hypoxia in hypoxia-tolerant rodents may provide a useful model for understanding BAT dysfunction in obesity.

Indeed, although environmental hypoxia is typically associated with high-altitude or subterranean habitats, a similar condition—tissue hypoxia—is a hallmark of metabolic disease in humans.^21,48 For example, in obesity, expansion of adipose tissue outpaces vascularization, leading to localized hypoxia within adipose depots.⁴⁹ This hypoxic environment triggers inflammation, fibrosis, and metabolic dysfunction, such as changes in glucose and lactate cycling, and also insulin resistance.⁵⁰ These changes are well documented in white adipocytes,⁵¹ but BAT is not immune to these effects. Reduced oxygen availability in adipose tissue can impair mitochondrial function, suppress thermogenesis, and contribute to decreased energy expenditure, among other effects. This creates a vicious cycle in which reduced BAT activity promotes positive energy balance, further exacerbating obesity.^52,53

Intriguingly, recent studies suggest that activating BAT or beiging of white fats may protect against obesity and obesity-related metabolic syndromes by helping to regulate pathways such as glucose and lipid homeostasis, although what impact these changes might have on thermoregulation in the long term remains undetermined.⁵⁴ Furthermore, declining BAT stores with age in humans limits the impact of activating BAT as a treatment strategy, pushing a greater focus onto beiging of white fats through cold exposure, diet, exercise, and so on, although many of these approaches are difficult to implement without significant lifestyle changes.^55,56

Another disease that may benefit from comparative research in this area is type 2 diabetes, which is characterized by insulin resistance, impaired glucose homeostasis, and altered energy metabolism.⁵⁷ Here, BAT has emerged as a potential therapeutic target due to its ability to increase energy expenditure, enhance glucose uptake, and improve lipid metabolism: active BAT consumes large amounts of glucose and fatty acids, contributing to improved systemic metabolic profiles.⁵⁸ In humans, increased BAT activity is associated with enhanced insulin sensitivity and reduced risk of metabolic disease.⁵⁹ Conversely, reduced BAT function is linked to obesity and diabetes.⁶⁰ Hypoxia-induced suppression of BAT may therefore play a significant role in the pathogenesis of metabolic disease by reducing thermogenic capacity and energy expenditure and thus contributing to positive energy balance and weight gain. Additionally, mitochondrial dysfunction in BAT can impair glucose utilization, exacerbating hyperglycemia and insulin resistance.⁶¹ Understanding the mechanisms by which hypoxia suppresses BAT function may reveal new therapeutic targets.⁶² For example, interventions aimed at restoring mitochondrial function, enhancing oxygen delivery, or modulating HIF signaling could potentially improve BAT activity and metabolic health.

Taken together, the divergent responses of BAT to hypoxia in hypoxia-intolerant laboratory vs hypoxia-tolerant African mole rats provide a powerful framework for understanding how mitochondrial function, energy expenditure, and whole-body metabolism can be integrated under conditions of oxygen limitation.² These differences are not merely quantitative but qualitative, reflecting fundamentally distinct regulatory strategies. This distinction can be conceptualized as constraint-driven vs control-driven suppression: in intolerant species, BAT function declines because it cannot be sustained; in certain tolerant species, it is actively turned off because it is not needed.

CONCLUSIONS AND FUTURE DIRECTIONS

BAT tissue is a central regulator of energy expenditure, but its function is highly dependent on oxygen availability. Environmental hypoxia imposes a fundamental constraint on BAT thermogenesis, forcing organisms to balance the energetic demands of heat production with the need to conserve oxygen for essential processes. In hypoxia-intolerant laboratory rodents, this challenge is met with incomplete and often maladaptive suppression of BAT activity, characterized by mitochondrial dysfunction, oxidative stress, and impaired metabolic regulation. In contrast, some hypoxia-tolerant social African rodents exhibit a highly coordinated and reversible suppression of BAT mitochondrial function, preserving cellular integrity while minimizing energy expenditure. These findings highlight the importance of mitochondrial regulation as a central determinant of physiological responses to hypoxia. They also underscore the potential of targeting BAT and mitochondrial function in the treatment of metabolic diseases such as type 2 diabetes. Ultimately, a deeper understanding of how BAT is regulated under hypoxia, particularly in hypoxia-tolerant rodents, will be essential for translating these insights into therapeutic strategies. Key areas for future research include molecular mechanisms of mitochondrial shutdown (what signaling pathways mediate the rapid and reversible suppression of mitochondrial activity in BAT?), the role of post-translational modifications (how are mitochondrial proteins, including UCP1 and ETC components, regulated at the post-translational level during hypoxia?), better integration with systemic physiology (how do neural, endocrine, and metabolic signals coordinate BAT suppression with whole-body energy balance?), and exploration of translational potential (can mechanisms identified in hypoxia-tolerant species be harnessed to treat metabolic disease or protect tissues from hypoxic injury?). Addressing these questions will require integrative approaches combining molecular biology, physiology, and comparative biology.

Abbreviations

ATP, adenosine triphosphate; BAT, brown adipose tissue, HIF, hypoxia-inducible factor; NST, nonshivering thermogenesis; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1α; UCP, uncoupling protein.

Author Contributions

MEP conceived of the paper. MEP and HC wrote and edited the paper and agree to be held responsible for the content.