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Genome-wide mapping of H3K4me1 status in primary adipocytes isolated from wild-type (WT) and Lonp1-knockout (LONP1 AKO) mice

ABSTRACT: Mitochondrial proteases are emerging as key regulators of mitochondrial plasticity acting both as protein quality surveillance and regulatory enzymes by performing highly regulated proteolytic reactions. It remains unclear, however, whether the regulated mitochondrial proteolysis is mechanistically linked to cell identity switch such as white-to-beige conversion of adipocytes. We found that disruption of LONP1-dependent proteolysis substantially impairs thermogenic molecular program and cellular respiration in in vitro differentiated primary adipocytes. qPCR analysis showed that expression levels of Ucp1 and other beige adipocyte thermogenic genes were remarkably downregulated in LONP1 AKO adipocytes. We took a deeper dive into the characterization of histone modifications in LONP1 AKO adipocytes using the global enhancer marker H3K4me1 ChIP-Seq. These unbiased ChIP seq data are strong evidence of that LONP1 loss results in decreased H3K4me1 on a broad array of thermogenic genes. These results collectively indicate that LONP1 is crucial to maintain proper epigenetic homeostasis and beige thermogenic gene expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE222490 | GEO | 2023/04/08

REPOSITORIES: GEO

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Project description:This experiment was conducted to identify the mitochondrial protein changes in the presence and absence of LONP1 in skeletal muscle. The following abstract from the submitted manuscript describes the major findings of this work.Disuse-associated loss of muscle LONP1 impairs mitochondrial quality and causes reduced skeletal muscle mass and strength. Zhisheng Xu, Tingting Fu, Qiqi Guo, Danxia Zhou, Wanping Sun, Zheng Zhou, Lin Liu, Liwei Xiao, Yujing Yin, Yuhuan Jia, Xin Pan, Lei Fang, Min-sheng Zhu, Wenyong Fei, Bin Lu and Zhenji Gan. Mitochondrial proteolysis is an evolutionarily conserved quality control mechanism to maintain proper mitochondrial integrity and function. However, the physiological relevance of stress-induced impaired mitochondrial protein quality remains unclear. Here, we demonstrate that LONP1, a major mitochondrial protease resides in the matrix, plays a critical role in controlling mitochondrial quality as well as skeletal muscle mass and strength in response to muscle disuse. In humans and mice, disuse-related muscle loss is associated with decreased mitochondrial LONP1 protein. Skeletal muscle-specific ablation of LONP1 in mice resulted in impaired mitochondrial protein turnover, leading to mitochondrial dysfunction. This caused reduced muscle fiber size and strength. Mechanistically, aberrant accumulation of mitochondrial-retained protein in muscle upon loss of LONP1 induces the activation of autophagy-lysosome degradation program of muscle loss. Overexpressing a mitochondrial-retained mutant ornithine transcarbamylase (ΔOTC), a known protein degraded by LONP1, in skeletal muscle induces mitochondrial dysfunction, autophagy activation, and cause muscle loss and weakness. Thus, these findings reveal a pivotal role of LONP1-dependent mitochondrial protein quality-control in safeguarding mitochondrial function and preserving skeletal muscle mass and strength, and unravel an intriguing link between mitochondrial protein quality and muscle mass maintenance during muscle disuse.

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Genome-wide mapping of H3K4me1 status in primary adipocytes isolated from wild-type (WT) and Lonp1-knockout (LONP1 AKO) mice

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