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Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis

Author

Listed:
  • Cecilia Patitucci

    (Université Paris Cité)

  • Juan Diego Hernández-Camacho

    (Université Paris Cité)

  • Elodie Vimont

    (Université Paris Cité)

  • Sonny Yde

    (Université Paris Cité)

  • Thomas Cokelaer

    (Université Paris Cité
    Université Paris Cité)

  • Thibault Chaze

    (Université Paris Cité)

  • Quentin Giai Gianetto

    (Université Paris Cité
    Université Paris Cité)

  • Mariette Matondo

    (Université Paris Cité)

  • Anastasia Gazi

    (Université Paris Cité)

  • Ivan Nemazanyy

    (SFR Necker, INSERM US24/CNRS UAR 3633)

  • David A. Stroud

    (University of Melbourne, Victorian Clinical Genetics Services and Murdoch Children’s Research Institute, Royal Children’s Hospital)

  • Daniella H. Hock

    (University of Melbourne, Victorian Clinical Genetics Services and Murdoch Children’s Research Institute, Royal Children’s Hospital)

  • Erminia Donnarumma

    (Université Paris Cité)

  • Timothy Wai

    (Université Paris Cité)

Abstract

Hepatic steatosis is the result of imbalanced nutrient delivery and metabolism in the liver and is the first hallmark of Metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is the most common chronic liver disease and involves the accumulation of excess lipids in hepatocytes, inflammation, and cancer. Mitochondria play central roles in liver metabolism yet the specific mitochondrial functions causally linked to MASLD remain unclear. Here, we identify Mitochondrial Fission Process 1 protein (MTFP1) as a key regulator of mitochondrial and metabolic activity in the liver. Deletion of Mtfp1 in hepatocytes is physiologically benign in mice yet leads to the upregulation of oxidative phosphorylation (OXPHOS) activity and mitochondrial respiration, independently of mitochondrial biogenesis. Consequently, liver-specific knockout mice are protected against high fat diet-induced steatosis and metabolic dysregulation. Additionally, Mtfp1 deletion inhibits mitochondrial permeability transition pore opening in hepatocytes, conferring protection against apoptotic liver damage in vivo and ex vivo. Our work uncovers additional functions of MTFP1 in the liver, positioning this gene as an unexpected regulator of OXPHOS and a therapeutic candidate for MASLD.

Suggested Citation

  • Cecilia Patitucci & Juan Diego Hernández-Camacho & Elodie Vimont & Sonny Yde & Thomas Cokelaer & Thibault Chaze & Quentin Giai Gianetto & Mariette Matondo & Anastasia Gazi & Ivan Nemazanyy & David A. , 2023. "Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44143-9
    DOI: 10.1038/s41467-023-44143-9
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