Proteolytic rewiring of mitochondria by LONP1 directs cell identity switching of adipocytes

Tingting Fu^#¹, Wanping Sun^#¹, Jiachen Xue^#¹, Zheng Zhou^#¹, Wen Wang², Qiqi Guo¹, Xinyi Chen¹, Danxia Zhou¹, Zhisheng Xu¹, Lin Liu¹, Liwei Xiao¹, Yan Mao¹, Likun Yang¹, Yujing Yin¹, Xue-Na Zhang³, Qiangyou Wan⁴, Bin Lu⁵, Yuncong Chen⁶, Min-Sheng Zhu³, Philipp E Scherer⁷, Lei Fang⁸, Hai-Long Piao², Mengle Shao⁹, Zhenji Gan^{10

11}

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing University, Nanjing, China.
² CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
³ State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing University, Nanjing, China.
⁴ CAS Key Laboratory of Molecular Virology and Immunology, The Center for Microbes, Development and Health, Chinese Academy of Sciences, Shanghai, China.
⁵ Hengyang Medical College, University of South China, Hengyang, China.
⁶ State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.
⁷ Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁸ Jiangsu Key Laboratory of Molecular Medicine, Chemistry and Biomedicine Innovation Center (ChemBIC), Medical School of Nanjing University, Nanjing, China.
⁹ CAS Key Laboratory of Molecular Virology and Immunology, The Center for Microbes, Development and Health, Chinese Academy of Sciences, Shanghai, China. mlshao@ips.ac.cn.
¹⁰ State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing University, Nanjing, China. ganzj@nju.edu.cn.
¹¹ Jiangsu Key Laboratory of Molecular Medicine, Chemistry and Biomedicine Innovation Center (ChemBIC), Medical School of Nanjing University, Nanjing, China. ganzj@nju.edu.cn.

^# Contributed equally.

PMID: 37217599
DOI: 10.1038/s41556-023-01155-3

Proteolytic rewiring of mitochondria by LONP1 directs cell identity switching of adipocytes

Tingting Fu et al. Nat Cell Biol. 2023 Jun.

. 2023 Jun;25(6):848-864.

doi: 10.1038/s41556-023-01155-3. Epub 2023 May 22.

Authors

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing University, Nanjing, China.
² CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
³ State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing University, Nanjing, China.
⁴ CAS Key Laboratory of Molecular Virology and Immunology, The Center for Microbes, Development and Health, Chinese Academy of Sciences, Shanghai, China.
⁵ Hengyang Medical College, University of South China, Hengyang, China.
⁶ State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.
⁷ Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁸ Jiangsu Key Laboratory of Molecular Medicine, Chemistry and Biomedicine Innovation Center (ChemBIC), Medical School of Nanjing University, Nanjing, China.
⁹ CAS Key Laboratory of Molecular Virology and Immunology, The Center for Microbes, Development and Health, Chinese Academy of Sciences, Shanghai, China. mlshao@ips.ac.cn.
¹⁰ State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing University, Nanjing, China. ganzj@nju.edu.cn.
¹¹ Jiangsu Key Laboratory of Molecular Medicine, Chemistry and Biomedicine Innovation Center (ChemBIC), Medical School of Nanjing University, Nanjing, China. ganzj@nju.edu.cn.

^# Contributed equally.

PMID: 37217599
DOI: 10.1038/s41556-023-01155-3

Abstract

Mitochondrial proteases are emerging as key regulators of mitochondrial plasticity and acting as both protein quality surveillance and regulatory enzymes by performing highly regulated proteolytic reactions. However, it remains unclear whether the regulated mitochondrial proteolysis is mechanistically linked to cell identity switching. Here we report that cold-responsive mitochondrial proteolysis is a prerequisite for white-to-beige adipocyte cell fate programming during adipocyte thermogenic remodelling. Thermogenic stimulation selectively promotes mitochondrial proteostasis in mature white adipocytes via the mitochondrial protease LONP1. Disruption of LONP1-dependent proteolysis substantially impairs cold- or β₃ adrenergic agonist-induced white-to-beige identity switching of mature adipocytes. Mechanistically, LONP1 selectively degrades succinate dehydrogenase complex iron sulfur subunit B and ensures adequate intracellular succinate levels. This alters the histone methylation status on thermogenic genes and thereby enables adipocyte cell fate programming. Finally, augmented LONP1 expression raises succinate levels and corrects ageing-related impairments in white-to-beige adipocyte conversion and adipocyte thermogenic capacity. Together, these findings reveal that LONP1 links proteolytic surveillance to mitochondrial metabolic rewiring and directs cell identity conversion during adipocyte thermogenic remodelling.

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Comment in

Mitoprotease LONP1 controls white-to-beige adipocyte conversion via metabolic enzyme turnover.
[No authors listed] [No authors listed] Nat Cell Biol. 2023 Jun;25(6):810-811. doi: 10.1038/s41556-023-01161-5. Nat Cell Biol. 2023. PMID: 37225967 No abstract available.

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Proteolytic rewiring of mitochondria by LONP1 directs cell identity switching of adipocytes

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Proteolytic rewiring of mitochondria by LONP1 directs cell identity switching of adipocytes

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