The role of Coiled-Coil-Helix-Coiled-coil-Helix Domain 10 (CHCHD10) in adipocyte biology

Abstract

<p><strong>Introduction: </strong>Coiled-Coil-Helix-Coiled-coil-Helix Domain 10 (Chchd10) is an inner mitochondrial membrane protein essential for maintaining the structure and function of mitochondria. <br></p><p><strong>Aims:</strong> Considering the typical role of mitochondria in modulating lipid metabolism and the significant reduction of Chchd10 in response to energy surplus condition identified in our previous study, here we aim to investigate whether Chchd10 modulates adipocyte biology by mediating lipid metabolism and the underlying mechanisms.<br></p><p><strong>Methods: </strong>Six-week-old male adipocyte-specific Chchd10 knockout (ATC10 KO) mice and their littermate controls (CTR) were subjected to HFD or standard chow diet (STC) feeding for 10 weeks. The subcutaneous white adipose tissue (scWAT) was subjected to RNA sequencing analysis. The underlying mechanism of Chchd10 in regulating lipid metabolism was further investigated using stromal vascular fraction-differentiated Chchd10 KO and control adipocytes.<br></p><p><strong>Results: </strong>The expression of Chchd10 was significantly reduced in the WAT of HFD-fed mice. In STC-fed mice, Chchd10 deficiency significantly increases the percentage of weight of scWAT in mice by 20%. On the contrary, Chchd10 deficiency protects mice from HFD-induced fat mass increase, insulin resistance, as well as excessive hepatic lipid accumulation. Gene set enrichment analysis of RNA sequencing data further recapitulates that Chchd10 deficiency activates adipogenic signalling pathways in STC-fed mice, while it enhances fatty acid degradation and TCA cycle activity in mitochondria of HFD-fed mice. Mechanistically, Chchd10 deficiency induces the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2). Enhanced nuclear NRF2 not only upregulates PPARγ/CEBPα-mediated adipogenic pathways but also activates the transcription of anti-oxidative gene glutathione S-transferase alpha 4 (GSTA4). Chchd10 deficiency enhances NRF2/PPARγ/CEBPα axis-mediated adipogenic signalling which in turn promotes lipid synthesis in adipocytes leading to increased WAT mass in STC-fed mice. Under HFD-fed condition, Chchd10 deficiency-induced NRF2 upregulates GSTA4 which in turn catalyses glutathione-mediated 4-hydroxynonenal clearance, thus protects adipocytes from lipid peroxidation-induced mitochondria injury. NRF2/GSTA4 axis-protected mitochondria in adipocytes of ATC10 KO mice combats excessive lipid accumulation therefore attenuates diet-induced obesity. <br></p><p><strong>Conclusion: </strong>CHCHD10 acts as a stress sensor in modulating adipocyte biology. Under normal condition, Chchd10 restricts NRF2-mediated adipogenic pathways. Under energy surplus condition, the reduction of Chchd10 activates NRF2-targeted anti-oxidative signaling pathways thereby attenuates obesity-related mitochondria injury.</p>