Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1

Abstract

Brown adipose tissue (BAT) can dissipate chemical energy as heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1)1,2. Thermogenesis from BAT and beige adipose can combat obesity and diabetes3, encouraging investigation of factors that control UCP1-dependent respiration in vivo. Herein we show that acutely activated BAT thermogenesis is defined by a substantial increase in mitochondrial reactive oxygen species (ROS) levels. Remarkably, this process supports in vivo BAT thermogenesis, as pharmacological depletion of mitochondrial ROS results in hypothermia upon cold exposure, and inhibits UCP1-dependent increases in whole body energy expenditure. We further establish that thermogenic ROS alter BAT cysteine thiol redox status to drive increased respiration, and Cys253 of UCP1 is a key target. UCP1 Cys253 is sulfenylated during thermogenesis, while mutation of this site desensitizes the purine nucleotide inhibited state of the carrier to adrenergic activation and uncoupling. These studies identify BAT mitochondrial ROS induction as a mechanism that drives UCP1-dependent thermogenesis and whole body energy expenditure, which opens the way to develop improved therapeutic strategies for combating metabolic disorders.

UCP1 deficiency causes brown fat respiratory chain depletion and sensitizes mitochondria to calcium overload-induced dysfunction

“…Evidence in support of a robust role for UCP1-mediated uncoupling in the regulation of ROS production in vitro has been provided (6,7,41), as have findings suggesting a limited role for UCP1 activity in controlling ROS in vitro (8,(42)(43)(44). Importantly, UCP1 appears to play a role in regulating BAT redox tone in vivo (9), and acute adrenergic stimulation in vivo drives ROS production to support UCP1-dependent thermogenesis (10).…”

“…For example, it is becoming increasingly evident that in specific respiratory states, UCP1 can reduce reactive oxygen species (ROS) levels in vitro (4)(5)(6)(7)(8)(9). The mitochondrial ETC is a major source of ROS production in the cell, and ROS play important roles in physiology and pathophysiology (10)(11)(12). Reverse electron transport (RET) through mitochondrial complex I is a key mechanism by which ROS are generated in vivo (11,13).…”

Stress turns on the heat: Regulation of mitochondrial biogenesis and UCP1 by ROS in adipocytes

“…24 Indeed, during acute or chronic cold acclimation in rodents, an elevation in ROS generation and a shift toward a more oxidized environment was observed in BAT and was associated with mitochondrial proliferation. [25][26][27][28] Furthermore, agents known to deplete glutathione (GSH) such as buthionine sulfoximine (BSO) increased the expression of PGC-1a both in WAT and in BAT. 29 In addition, ROS in the form of H 2 O 2 was shown to directly induce the expression of PGC-1a and PGC-1b in brown-fat fibroblasts through a mechanism involving the Cre-binding protein (CREB).…”

Uncoupling protein 1 controls reactive oxygen species in brown adipose tissue

“…11). Other studies have reported that this feedback mechanism does not exist (12)(13)(14) (18). Although some critiques remain (19), the issue of whether specific ROS-mediated UCP1 modifications possess physiological relevance may only be settled by expanding analysis, e.g., introducing critical ROS-modified amino acids using in vivo CRISPR/ Cas approaches.…”

“…The answer is not clear so far. An UCP1 ortholog, distinct from its paralogs UCP2 and UCP3, must have existed before the divergence of lobe-and ray-finned vertebrates more than 420 million years ago because UCP1 is found (18). In the wild-type condition, increased ROS levels are mitigated by higher UCP1 activity (9, 10).…”