Abstract
Mitochondrial retrograde signaling plays crucial roles in maintaining metabolic homeostasis via regulating genome modification and oxidative responsive gene expression. In this study, we identified GCN5L1, a protein localized in both mitochondria and cytoplasm, and demonstrated its specific translocation from mitochondria to cytoplasm during lipid overload and high-fat diet feeding. Using transcriptome and proteome analyses, we identified that cytoplasmic GCN5L1 binds to and promotes the acetylation of PPARγ at lysine 289 (K289). This acetylation protected PPARγ from ubiquitination-mediated degradation by proteasome. GCN5L1 translocation enhanced protein stability of PPARγ and subsequently promoted lipid accumulation in both cultured cells and murine models. Our study further reveals that PPARγ-K289 mutation reduces the ubiquitination of PPARγ and exacerbates liver steatosis in mice. These findings unveil a mitochondrial retrograde signaling during lipid overload, which regulates the crucial lipogenic transcriptional factor. This discovery elucidates an unrecognized mitochondrial function and mechanism underlying hepatic lipid synthesis.
Authors
Jiaqi Zhang, Danni Wang, Qiqi Tang, Yaoshu Yue, Xin Lu, Xiuya Hu, Yitong Han, Jiarun Chen, Zihan Wang, Xue Bai, Kai Zhang, Yongsheng Chang, Longhao Sun, Lu Zhu, Lingdi Wang
Figure 1
GCN5L1 accumulates in cytoplasm during development of MASLD in both HFD-fed mice and MASLD patients.
