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FAM3A maintains metabolic homeostasis by interacting with F1-ATP synthase to regulate the activity and assembly of ATP synthase

  • Author Footnotes
    1 These authors contributed equally to this work.
    Han Yan
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Yuhong Meng
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Xin Li
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
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  • Rui Xiang
    Affiliations
    Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
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  • Song Hou
    Affiliations
    Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
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  • Junpei Wang
    Affiliations
    Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
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  • Lin Wang
    Affiliations
    Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an 710032, China
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  • Xiaoxing Yu
    Affiliations
    Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
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  • Ming Xu
    Affiliations
    Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Beijing 100191, China
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  • Yujing Chi
    Correspondence
    Corresponding authors.
    Affiliations
    Department of Central Laboratory and Institute of Clinical Molecular Biology, Peking University People's Hospital, Beijing 100044, China
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  • Jichun Yang
    Correspondence
    Corresponding authors.
    Affiliations
    Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
Published:December 02, 2022DOI:https://doi.org/10.1016/j.metabol.2022.155372

      Highlights

      • FAM3A is a new active component of ATPS.
      • FOXD3 is revealed to be a general transcription factor that controls ATPS assembly.
      • FAM3A-ATPS-FOXD3 regulation loop plays important roles in controlling ATPS assembly and capacity.
      • Identification of FAM3A-FOXD3 axis makes it possible and viable to restore ATPS capacity by activating one single gene.
      • Activation of FAM3A-FOXD3 axis represents a novel strategy for the treatment of metabolic disorders.

      Abstract

      Reduced mitochondrial ATP synthase (ATPS) capacity plays crucial roles in the pathogenesis of metabolic disorders. However, there is currently no effective strategy for synchronously stimulating the expressions of ATPS key subunits to restore its assembly. This study determined the roles of mitochondrial protein FAM3A in regulating the activity and assembly of ATPS in hepatocytes. FAM3A is localized in mitochondrial matrix, where it interacts with F1-ATPS to initially activate ATP synthesis and release, and released ATP further activates P2 receptor-Akt-CREB pathway to induce FOXD3 expression. FOXD3 synchronously stimulates the transcriptions of ATPS key subunits and assembly genes to increase its assembly and capacity, augmenting ATP synthesis and inhibiting ROS production. FAM3A, FOXD3 and ATPS expressions were reduced in livers of diabetic mice and NAFLD patients. FOXD3 expression, ATPS capacity and ATP content were reduced in various tissues of FAM3A-deficient mice with dysregulated glucose and lipid metabolism. Hepatic FOXD3 activation increased ATPS assembly to ameliorate dysregulated glucose and lipid metabolism in obese mice. Hepatic FOXD3 inhibition or knockout reduced ATPS capacity to aggravate HFD-induced hyperglycemia and steatosis. In conclusion, FAM3A is an active ATPS component, and regulates its activity and assembly by activating FOXD3. Activating FAM3A-FOXD3 axis represents a viable strategy for restoring ATPS assembly to treat metabolic disorders.

      Graphical abstract

      Abbreviations:

      AMPK (adenosine 5′-monophosphate (AMP)-activated protein kinase), ATP (adenosine triphosphate), ATP11 (ATPS mitochondrial F1 complex assembly factor 1), ATP12 (ATPS mitochondrial F1 complex assembly factor 2), ATP23 (mitochondrial inner membrane protease ATP23 homolog), ATP6 (ATPS Fo subunit 6), ATPS (ATP Synthase), ATPSb (ATPS b subunit), ATPSc (ATPS c subunit), ATPSd (ATPS d subunit), ATPSα (ATPS α subunit), ATPSβ (ATPS β subunit), ATPSγ (ATPS γ subunit), ATPSδ (ATPS δ subunit), ATPSε (ATPS ε subunit), CaM (calmodulin), ChIP (chromatin immunoprecipitation), CHO (cholesterol), CoIP (Co-Immunoprecipitation), Complex IV (cytochrome c oxidase subunit IV), CREB (cAMP response element binding protein), DNP (2,4-dinitrophenol), EPA (eicosapentaenoic acid), FAM3 (family with sequence similarity 3), FCCP (carbonylcyanide-p-trifluoromethoxyphenylhydrazone), FFAs (free fatty acids), FOXD3 (forkhead box protein D3), FOXO1 (forkhead box protein O1), HCC (hepatocellular carcinoma), HFD (high fat diet), ITT (insulin tolerance tests), MMP (mitochondrial membrane potential), NAFLD (non-alcoholic fatty liver disease), ND (normal diet), OGTT (oral glucose tolerance tests), pAkt (phosphorylated Akt), PEPCK (phosphoenolpyruvate carboxykinase), PTT (pyruvate tolerance tests), ROS (reactive oxygen species), SDS (sodium dodecyl sulfonate), TG (triglyceride), TMEM70 (transmembrane protein 70), TOM20 (translocase of the outer membrane 20)

      Keywords

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