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F-ATP synthase inhibitory factor 1 regulates metabolic reprogramming involving its interaction with c-Myc and PGC1α.

ABSTRACT: F-ATP synthase inhibitory factor 1 (IF1) is an intrinsic inhibitor of F-ATP synthase. It is known that IF1 mediates metabolic phenotypes and cell fate, yet the molecular mechanisms through which IF1 fulfills its physiological functions are not fully understood. Ablation of IF1 favors metabolic switch to oxidative metabolism from glycolysis. c-Myc and PGC1α are critical for metabolic reprogramming. This work identified that IF1 interacted with Thr-58 phosphorylated c-Myc, which might thus mediate the activity of c-Myc and promote glycolysis. The interaction of IF1 with PGC1α inhibited oxidative respiration. c-Myc and PGC1α were localized to mitochondria under mitochondrial stress in an IF1-dependent manner. Furthermore, IF1 was found to be required for the protective effect of hypoxia on c-Myc- and PGC1α-induced cell death. This study suggested that the interactions of IF1 with transcription factors c-Myc and PGC1α might be involved in IF1-regulatory metabolic reprogramming and cell fate.

SUBMITTER: Guo L

PROVIDER: S-EPMC10352482 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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F-ATP synthase inhibitory factor 1 regulates metabolic reprogramming involving its interaction with c-Myc and PGC1α.

Guo Lishu L Gu Zhenglong Z

Frontiers in oncology 20230703

F-ATP synthase inhibitory factor 1 (IF1) is an intrinsic inhibitor of F-ATP synthase. It is known that IF1 mediates metabolic phenotypes and cell fate, yet the molecular mechanisms through which IF1 fulfills its physiological functions are not fully understood. Ablation of IF1 favors metabolic switch to oxidative metabolism from glycolysis. c-Myc and PGC1α are critical for metabolic reprogramming. This work identified that IF1 interacted with Thr-58 phosphorylated c-Myc, which might thus mediate ...[more]

PMID: 37469400

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Project description:The receptor kinase c-MET has emerged as a target for glioblastoma therapy. However, treatment resistance emerges inevitably. Here, we performed global metabolite screening with metabolite set enrichment coupled with transcriptome and gene set enrichment analysis and proteomic screening, and identified substantial reprogramming of tumor metabolism involving oxidative phosphorylation and fatty acid oxidation (FAO) with substantial accumulation of acyl-carnitines accompanied by an increase of PGC1α in response to genetic (shRNA and CRISPR/Cas9) and pharmacologic (crizotinib) inhibition of c-MET. Extracellular flux and carbon tracing analyses (U-13C-glucose, U-13C-glutamine, and U-13C-palmitic acid) demonstrated enhanced oxidative metabolism, which was driven by FAO and supported by increased anaplerosis of glucose carbons. These findings were observed in concert with increased number and fusion of mitochondria and production of reactive oxygen species. Genetic interference with PGC1α rescued this oxidative phenotype driven by c-MET inhibition. Silencing and chromatin immunoprecipitation experiments demonstrated that cAMP response elements binding protein regulates the expression of PGC1α in the context of c-MET inhibition. Interference with both oxidative phosphorylation (metformin, oligomycin) and β-oxidation of fatty acids (etomoxir) enhanced the antitumor efficacy of c-MET inhibition. Synergistic cell death was observed with c-MET inhibition and gamitrinib treatment. In patient-derived xenograft models, combination treatments of crizotinib and etomoxir, and crizotinib and gamitrinib were significantly more efficacious than single treatments and did not induce toxicity. Collectively, we have unraveled the mechanistic underpinnings of c-MET inhibition and identified novel combination therapies that may enhance its therapeutic efficacy. SIGNIFICANCE: c-MET inhibition causes profound metabolic reprogramming that can be targeted by drug combination therapies.

Dataset Information

F-ATP synthase inhibitory factor 1 regulates metabolic reprogramming involving its interaction with c-Myc and PGC1α.

Publications

F-ATP synthase inhibitory factor 1 regulates metabolic reprogramming involving its interaction with c-Myc and PGC1α.

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