SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.

Autor:	Yan W; 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., Xie C; 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., Sun S; 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.; Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080, Shanghai, China., Zheng Q; Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China., Wang J; Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080, Shanghai, China., Wang Z; Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, 200032, Shanghai, China., Man CH; Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China., Wang H; Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080, Shanghai, China., Yang Y; Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 250012, Jinan, China., Wang T; Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China., Shi L; 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., Zhang S; 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., Huang C; Department of Gastrointestinal Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080, Shanghai, China. huangchen0204@sjtu.edu.cn., Xu S; Department of Hematology, Southwest Hospital, Army Medical University, 400038, Chongqing, China. xushuangnian@tmmu.edu.cn., Wang YP; 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.; Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, 200032, Shanghai, China. yiping.wang1@shgh.cn.
Jazyk:	angličtina
Zdroj:	The EMBO journal [EMBO J] 2024 Jun; Vol. 43 (12), pp. 2337-2367. Date of Electronic Publication: 2024 Apr 22.
DOI:	10.1038/s44318-024-00101-9
Abstrakt:	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. (© 2024. The Author(s).)
Databáze:	MEDLINE
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