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Mitochondrial uncoupling, energy substrate utilization, and brown adipose tissue as therapeutic targets in cancer

Ragni, Maurizio, Ruocco, Chiara, Nisoli, Enzo·2025·npj Metabolic Health and Disease
DOI 10.1038/s44324-025-00080-3PMC PMC12454651
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Abstract

Mitochondria play a central role in regulating cellular energy metabolism, redox homeostasis, and biosynthesis. Mitochondrial uncoupling, through the alteration in the permeability of the inner mitochondrial membrane (IMM) to the leak of protons without adenosine triphosphate (ATP) synthesis, regulates thermogenesis, glucose and lipid metabolism, and reactive oxygen species (ROS) generation. In brown adipose tissue (BAT), proton leak via uncoupling protein 1 (UCP1) is essential for thermogenesis and has been shown to improve systemic glucose homeostasis, and recent studies indicate that BAT activation can also suppress tumor growth by competing with cancer cells for glucose. Several small-molecule mitochondrial uncouplers have demonstrated anticancer effects in preclinical models, although endogenous UCPs—particularly UCP2—are often upregulated in tumors, where they may support tumor growth by buffering ROS and increasing metabolic flexibility. These seemingly contradictory observations highlight the context-dependent effects of mitochondrial uncoupling in cancer. Here, we review current understanding of mitochondrial uncoupling mechanisms, the roles of UCP isoforms, and the metabolic interplay between BAT, cancer cells, and the tumor microenvironment, with a focus on therapeutic implications.

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Figures

Fig. 1 Mitochondrial oxidative phosphorylation. Nutrients are oxidized in mitochondrial matrix to generate a transmembrane electrochemical gradient, which is used for ATP synthesis, whose thermodynamic driving is maintained by ANT. Complexes I and II oxidize NADH and FADH2, respectively, which are generated by the oxidation of energy substrates in the tricarboxylic acid (TCA) cycle. Electrons (2e-) are transferred along the electron transport chain (ETC), due to increasing redox potentials of mitochondrial complexes. The energy released is used by Complexes I, III, and IV to pump protons into the intermembrane space (IMS), generating a proton gradient—also known as the protonmotive force—across the inner mitochondrial membrane. Energy derived from re-entry of protons into the matrix via ATP synthase (Complex V) drives ATP synthesis. The adenine nucleotide translocase (ANT) facilitates the exchange of matrix-derived ATP for cytosolic ADP, maintaining the ATP synthesis reaction far from thermodynamic equilibrium. IMS: intermembrane space. See main text for additional abbreviations. Image adapted from Servier Medical Art (https://smart.servier.com/), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).
Fig. 1 Mitochondrial oxidative phosphorylation. Nutrients are oxidized in mitochondrial matrix to generate a transmembrane electrochemical gradient, which is used for ATP synthesis, whose thermodynamic driving is maintained by ANT. Complexes I and II oxidize NADH and FADH2, respectively, which are generated by the oxidation of energy substrates in the tricarboxylic acid (TCA) cycle. Electrons (2e-) are transferred along the electron transport chain (ETC), due to increasing redox potentials of mitochondrial complexes. The energy released is used by Complexes I, III, and IV to pump protons into the intermembrane space (IMS), generating a proton gradient—also known as the protonmotive force—across the inner mitochondrial membrane. Energy derived from re-entry of protons into the matrix via ATP synthase (Complex V) drives ATP synthesis. The adenine nucleotide translocase (ANT) facilitates the exchange of matrix-derived ATP for cytosolic ADP, maintaining the ATP synthesis reaction far from thermodynamic equilibrium. IMS: intermembrane space. See main text for additional abbreviations. Image adapted from Servier Medical Art (https://smart.servier.com/), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).CC BY · PubMed Central
Fig. 2 Mechanisms of mitochondrial proton leak. Basal and inducible mitochondrial proton leak are involved in distinct processes of cell bioenergetic, regulating BMR/oxidative stress or BAT thermogenesis, respectively. Inducible proton leak is catalyzed by UCP1 in BAT, resulting in heat production. In contrast, basal proton leak is primarily mediated by ANT in non-BAT tissues. One model suggests that both inducible and basal proton leak are both protein-mediated processes that share a common mechanism involving free fatty acids (FFAs) as essential cofactors and proton carriers. An alternative model proposes that basal proton leak arises from increased permeability of the inner mitochondrial membrane (IMM), driven by changes in its phospholipid composition. In all cases, dissipation of the mitochondrial membrane potential (Δψ) leads to increased O2 consumption and energy expenditure to restore Δψ. This mechanism underlies adaptive thermogenesis (via UCP1), and may also contribute to basal metabolic rate (via ANT or membrane composition) and oxidative stress resistance (via “mild” uncoupling). See main text for abbreviations. Image adapted from Servier Medical Art (https://smart.servier.com/), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).
Fig. 2 Mechanisms of mitochondrial proton leak. Basal and inducible mitochondrial proton leak are involved in distinct processes of cell bioenergetic, regulating BMR/oxidative stress or BAT thermogenesis, respectively. Inducible proton leak is catalyzed by UCP1 in BAT, resulting in heat production. In contrast, basal proton leak is primarily mediated by ANT in non-BAT tissues. One model suggests that both inducible and basal proton leak are both protein-mediated processes that share a common mechanism involving free fatty acids (FFAs) as essential cofactors and proton carriers. An alternative model proposes that basal proton leak arises from increased permeability of the inner mitochondrial membrane (IMM), driven by changes in its phospholipid composition. In all cases, dissipation of the mitochondrial membrane potential (Δψ) leads to increased O2 consumption and energy expenditure to restore Δψ. This mechanism underlies adaptive thermogenesis (via UCP1), and may also contribute to basal metabolic rate (via ANT or membrane composition) and oxidative stress resistance (via “mild” uncoupling). See main text for abbreviations. Image adapted from Servier Medical Art (https://smart.servier.com/), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).CC BY · PubMed Central
Fig. 3 Regulation of body weight by energy balance. Body weight is determined by the balance between energy input and energy output. Input includes food intake or energy stores in white adipose tissue (WAT), while output is set by total energy expenditure (TEE), which comprises basal metabolic rate (BMR), physical activity, and thermogenesis—both obligatory and adaptive. Obligatory thermogenesis refers to the thermic effect of food, while adaptive thermogenesis includes both cold-induced and diet-induced thermogenesis. A sustained negative energy balance—where energy expenditure exceeds intake—lead to weight loss. Conversely, excessive energy intake not balanced by increased expenditure results in body weight gain. Image adapted from Servier Medical Art (https://smart.servier.com/), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).
Fig. 3 Regulation of body weight by energy balance. Body weight is determined by the balance between energy input and energy output. Input includes food intake or energy stores in white adipose tissue (WAT), while output is set by total energy expenditure (TEE), which comprises basal metabolic rate (BMR), physical activity, and thermogenesis—both obligatory and adaptive. Obligatory thermogenesis refers to the thermic effect of food, while adaptive thermogenesis includes both cold-induced and diet-induced thermogenesis. A sustained negative energy balance—where energy expenditure exceeds intake—lead to weight loss. Conversely, excessive energy intake not balanced by increased expenditure results in body weight gain. Image adapted from Servier Medical Art (https://smart.servier.com/), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).CC BY · PubMed Central
Fig. 4 Interplay between BAT, cancer metabolism, and mitochondrial uncoupling. Glucose addiction and high ΔΨ of cancers can be exploited for therapeutic purposes by means of endogenous BAT activation or exogenous uncouplers. Both cancer cells and activated BAT rely on high glucose utilization. Physiological (e.g., cold exposure) or pharmacological (e.g., β3-adrenergic agonists) activation of BAT promotes glucose utilization, acting as a metabolic “sink” that deprives cancer cells of glucose, thereby limiting tumor growth. Dietary supplementation with essential amino acids (EAAs), known to stimulate BAT, may also represent a nutritional anticancer strategy. Alternatively, exogenous small-molecule mitochondrial uncouplers have demonstrated anticancer effects by disrupting oxidative phosphorylation. See main text for abbreviations. Image adapted from Servier Medical Art (https://smart.servier.com/), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).
Fig. 4 Interplay between BAT, cancer metabolism, and mitochondrial uncoupling. Glucose addiction and high ΔΨ of cancers can be exploited for therapeutic purposes by means of endogenous BAT activation or exogenous uncouplers. Both cancer cells and activated BAT rely on high glucose utilization. Physiological (e.g., cold exposure) or pharmacological (e.g., β3-adrenergic agonists) activation of BAT promotes glucose utilization, acting as a metabolic “sink” that deprives cancer cells of glucose, thereby limiting tumor growth. Dietary supplementation with essential amino acids (EAAs), known to stimulate BAT, may also represent a nutritional anticancer strategy. Alternatively, exogenous small-molecule mitochondrial uncouplers have demonstrated anticancer effects by disrupting oxidative phosphorylation. See main text for abbreviations. Image adapted from Servier Medical Art (https://smart.servier.com/), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).CC BY · PubMed Central

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Cited by

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Metadata

Authors
Ragni, M., Ruocco, C., & Nisoli, E.
Venue
npj Metabolic Health and Disease
Publisher
Springer Science and Business Media LLC
Published
2025-09-22
Volume
3
Issue
1
ISSN
2948-2828
DOI
10.1038/s44324-025-00080-3
PMC
PMC12454651
Cited by
16
References
18
Language
en
Licence
Funders
  • National Recovery and Resilience Plan (SOE_0000181)
  • PRIN (20205X4C9E)

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