Mitophagy is required for brown adipose tissue mitochondrial homeostasis during cold challenge

Abstract

Brown adipose tissue (BAT) is a specialized thermogenic organ in mammals. The ability of BAT mitochondria to generate heat in response to cold-challenge to maintain core body temperature is essential for organismal survival. While cold activated BAT mitochondrial biogenesis is recognized as critical for thermogenic adaptation, the contribution of mitochondrial quality control to this process remains unclear. Here, we show mitophagy is required for brown adipocyte mitochondrial homeostasis during thermogenic adaptation. Mitophagy is significantly increased in BAT from cold-challenged mice (4 °C) and in β-agonist treated brown adipocytes. Blockade of mitophagy compromises brown adipocytes mitochondrial oxidative phosphorylation (OX-PHOS) capacity, as well as BAT mitochondrial integrity. Mechanistically, cold-challenge induction of BAT mitophagy is UCP1-dependent. Furthermore, our results indicate that mitophagy coordinates with mitochondrial biogenesis, maintaining activated BAT mitochondrial homeostasis. Collectively, our in vivo and in vitro findings identify mitophagy as critical for brown adipocyte mitochondrial homeostasis during cold adaptation.

Breast milk alkylglycerols sustain beige adipocytes through adipose tissue macrophages

“…BeAT development is associated with increased mitochondrial content and uncoupling, which can have unfavorable outcomes when it occurs in excess (63,64). The expansion of the mitochondrial network is thus maintained in a physiological range by signals that remain the subject of intense research (65,66). It is intriguing that AKGs had an effect only in neonates and in adult obese mice and were ineffective in lean adult mice.…”

“…The adipocyte effect of NPFF was due to its binding to NPFFR1, which was expressed by 3T3-L1 adipocytes (Supplemental Figure 15I). Autophagy allows metabolic adaptation (72), and it coordinates with mitochondrial biogenesis to maintain healthy metabolism (65,66,73).…”

Thermogenesis in Adipose Tissue Activated by Thyroid Hormone

“…Mice with an adipose-specific impairment of autophagy have more mitochondria in their adipose tissue [97] suggesting that autophagy is essential for mitochondrial clearance in the BAT. At present, it is still controversial how autophagy in the BAT is regulated during the adaptive thermogenesis, since both autophagy inhibition and induction have been observed upon cold exposure [98][99][100]. Nevertheless, mitophagy in the BAT is important to maintain mitochondrial quality control during thermogenesis [22,99].…”

“…At present, it is still controversial how autophagy in the BAT is regulated during the adaptive thermogenesis, since both autophagy inhibition and induction have been observed upon cold exposure [98][99][100]. Nevertheless, mitophagy in the BAT is important to maintain mitochondrial quality control during thermogenesis [22,99]. T 3 directly stimulates mitophagy in the BAT in order to prevent oxidative damage in the cells.…”

The S100B Protein and Partners in Adipocyte Response to Cold Stress and Adaptive Thermogenesis: Facts, Hypotheses, and Perspectives

“…By tethering the external and internal mitochondrial membranes and mitochondrial channel components Tom40 and Tim23, ATAD3A is also able to facilitate the transport and degradation of the pro-apoptotic Pink1 protein within the mitochondrial matrix, leading to the down-regulation of parkin-dependent mitophagy, a key E3 ubiquitin–protein ligase [ 59 , 60 ]. Because mitophagy is an important function to maintain appropriate mitochondrial homeostasis in BAT [ 64 ], studies on the relationship among S100B levels, ATAD3A processing, and the regulation of Parkin-dependent mitophagy is another molecular pathway that should be considered to provide a better understanding of the contribution of S100B in BAT differentiation.…”