CoQ Regulates Brown Adipose Tissue Respiration and Uncoupling Protein 1 Expression

Abstract

Coenzyme Q (CoQ, aka ubiquinone) is a key component of the mitochondrial electron transport chain (ETC) and membrane-incorporated antioxidant. CoQ10 deficiencies encompass a heterogeneous spectrum of clinical phenotypes and can be caused by hereditary mutations in the biosynthesis pathway or result from pharmacological interventions such as HMG-CoA Reductase inhibitors, and statins, which are widely used to treat hypercholesterolemia and prevent cardiovascular disease. How CoQ deficiency affects individual tissues and cell types, particularly mitochondrial-rich ones such as brown adipose tissue (BAT), has remained poorly understood. Here we show that pharmacological and genetic models of BAT CoQ deficiency show altered respiration that can only in part be explained by classical roles of CoQ in the respiration chain. Instead, we found that CoQ strongly impacts brown and beige adipocyte respiration via the regulation of uncoupling protein 1 (UCP1) expression. CoQ deficiency in BAT robustly decreases UCP1 protein levels and uncoupled respiration unexpectedly, resulting in increased inner mitochondrial membrane potential and decreased ADP/ATP ratios. Suppressed UCP1 expression was also observed in a BAT-specific in vivo model of CoQ deficiency and resulted in enhanced cold sensitivity. These findings demonstrate an as yet unappreciated role of CoQ in the transcriptional regulation of key thermogenic genes and functions.

A comparative assessment of reference genes in mouse brown adipocyte differentiation and thermogenesis in vitro

“…Therefore, understanding the molecular mechanisms behind these events is essential to evaluate the physiological significance and potential therapeutic implications of brown adipose tissues in metabolic disorders and obesity-related conditions. Many studies using mouse models and brown adipogenesis suggest that they could be utilized to develop a new potential therapy by regulating adipose tissue browning and thermogenic activity [ 9 , 38 , 39 ]. In this study, we generated immortalized brown preadipocytes isolated from the interscapular BAT of Ucp1-luciferase transgenic mice and performed gene expression analysis during brown adipogenesis in vitro.…”

The Effect of Coenzyme Q10 Supplementation on Bile Acid Metabolism: Insights from Network Pharmacology, Molecular Docking, and Experimental Validation

“…[1] Recent studies have highlighted CoQ10's importance in maintaining the adaptive thermogenesis and the normal morphology and physiology of brown adipose tissue, which also shows promise in ameliorating glucolipid dysmetabolism and obesity. [2][3][4] Our previous study also demonstrated that CoQ10 improved obesity and metabolic disorders induced by a high-fat diet in mice (Figures S1 and S2, Supporting Information). However, the mechanism by which CoQ10 exerts its beneficial effects is not clear.…”

Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis

“…We previously showed that BAT CoQ uptake hinges on the scavenger receptor CD36, revealing that the absence of CD36 leads to cold-intolerance (Anderson et al, 2015 ), emphasizing the significance of CoQ in BAT and thermogenesis. We also uncovered an unexpected role for CoQ in the transcriptional regulation of pivotal thermogenic genes like UCP1, affecting uncoupled respiration and leading to a rise in the inner mitochondrial membrane potential and a decline in ADP/ATP ratios (Chang et al, 2022 ). These insights prompted us to delve deeper into the effects of CoQ deficiency in BAT.…”

“…We previously found that CoQ deficiency in brown adipose tissue resulted in lower oxygen consumption rates due to suppression of uncoupling protein 1 (UCP1) expression (Chang et al, 2022 ). To further define the transcriptional signature of CoQ deficiency, we performed RNA sequencing (RNAseq) analysis of mature brown adipocytes treated with 4-chlorobenzoic acid (4CBA), a polyprenyl-diphosphate:4-HB transferase (COQ2) inhibitor to block CoQ biosynthesis, or vehicle for 24 h. Analysis of the predicted subcellular locations of the top 50 upregulated and top 50 downregulated genes revealed that 4CBA treatment affected proteins in multiple organelles.…”

“…To examine BAT CoQ deficiency in vivo, we used a brown/beige fat-specific knockout of the CoQ synthesis enzyme decaprenyl diphosphate synthase subunit 2 (PDSS2) by crossing UCP1-cre animals with a PDSS2 Flox (Peng et al, 2008 ) strain, both in the C57 background, generating the PDSS2 BKO line. This model has previously been shown to have a 75% reduction in brown adipose tissue (BAT) CoQ levels, compared to floxed controls (PDSS2 FL ), while other tissue types are unaffected, resulting in UCP1 suppression in BAT (Chang et al, 2022 ). The knockout was verified by measuring that PDSS2 gene expression was decreased in BAT, but not other organs such as liver (Figure EV1F ).…”