2. Academic Validation
  3. SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression

SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression

  • EMBO J. 2024 Apr 22. doi: 10.1038/s44318-024-00101-9.
Weiwei Yan # 1,  Chengmei Xie # 1,  Sijun Sun # 1 2,  Quan Zheng # 3,  Jingyi Wang 4,  Zihao Wang 5,  Cheuk-Him Man 6,  Haiyan Wang 4,  Yunfan Yang 7,  Tianshi Wang 8,  Leilei Shi 1,  Shengjie Zhang 9,  Chen Huang 10,  Shuangnian Xu 11,  Yi-Ping Wang 12 13
Affiliations

Affiliations

  • 1 Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080, Shanghai, China.
  • 2 Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080, Shanghai, China.
  • 3 Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 4 Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080, Shanghai, China.
  • 5 Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, 200032, Shanghai, China.
  • 6 Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
  • 7 Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 250012, Jinan, China.
  • 8 Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
  • 9 Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080, Shanghai, China. shengjie.zhang@shgh.cn.
  • 10 Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080, Shanghai, China. huangchen0204@sjtu.edu.cn.
  • 11 Department of Hematology, Southwest Hospital, Army Medical University, 400038, Chongqing, China. xushuangnian@tmmu.edu.cn.
  • 12 Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080, Shanghai, China. yiping.wang1@shgh.cn.
  • 13 Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, 200032, Shanghai, China. yiping.wang1@shgh.cn.
  • # Contributed equally.
PMID: 38649537 DOI: 10.1038/s44318-024-00101-9
Abstract

Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle Enzyme succinate-CoA Ligase SUCLG1 strongly correlates with ETC genes across various TCGA Cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to Cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and Cancer development.

Keywords

FMS-like Tyrosine Kinase 3; Lysine Succinylation; Mitochondrial Biogenesis; Mitochondrial RNA Polymerase; Succinate-CoA Ligase.

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