RESUMO
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.
Assuntos
Biogênese de Organelas , Succinato-CoA Ligases , Animais , Humanos , Camundongos , Acil Coenzima A/metabolismo , Acil Coenzima A/genética , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , DNA Mitocondrial/metabolismo , DNA Mitocondrial/genética , RNA Polimerases Dirigidas por DNA/metabolismo , RNA Polimerases Dirigidas por DNA/genética , Leucemia/metabolismo , Leucemia/genética , Leucemia/patologia , Mitocôndrias/metabolismo , Mitocôndrias/genética , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Succinato-CoA Ligases/metabolismo , Succinato-CoA Ligases/genéticaRESUMO
Hematopoietic stem cells (HSCs) are multipotent stem cells that can self-renew and generate all blood cells of different lineages. The system is under tight control in order to maintain a precise equilibrium of the HSC pool and the effective production of mature blood cells to support various biological activities. Cell metabolism can regulate different molecular activities, such as epigenetic modification and cell cycle regulation, and subsequently affects the function and maintenance of HSC. Upon malignant transformation, oncogenic drivers in malignant hematopoietic cells can remodel the metabolic pathways for supporting the oncogenic growth. The dysregulation of metabolism results in oncogene addiction, implying the development of malignancy-specific metabolism-targeted therapy. In this chapter, we will discuss the significance of different metabolic pathways in hematopoiesis, specifically, the distinctive metabolic dependency in hematopoietic malignancies and potential metabolic therapy.