2. Academic Validation
  3. Liver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism

Liver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism

  • Cell Metab. 2023 Aug 8;35(8):1356-1372.e5. doi: 10.1016/j.cmet.2023.06.015.
Jee Hyung Sohn 1,  Beste Mutlu 1,  Pedro Latorre-Muro 1,  Jiaxin Liang 1,  Christopher F Bennett 1,  Kfir Sharabi 1,  Noa Kantorovich 1,  Mark Jedrychowski 2,  Steven P Gygi 2,  Alexander S Banks 3,  Pere Puigserver 4
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 2 Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 3 Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: pere_puigserver@dfci.harvard.edu.
PMID: 37473754 DOI: 10.1016/j.cmet.2023.06.015
Abstract

Liver mitochondria undergo architectural remodeling that maintains energy homeostasis in response to feeding and fasting. However, the specific components and molecular mechanisms driving these changes and their impact on energy metabolism remain unclear. Through comparative mouse proteomics, we found that fasting induces strain-specific mitochondrial cristae formation in the liver by upregulating MIC19, a subunit of the MICOS complex. Enforced MIC19 expression in the liver promotes cristae formation, mitochondrial respiration, and fatty acid oxidation while suppressing gluconeogenesis. Mice overexpressing hepatic MIC19 show resistance to diet-induced obesity and improved glucose homeostasis. Interestingly, MIC19 overexpressing mice exhibit elevated energy expenditure and increased pedestrian locomotion. Metabolite profiling revealed that uracil accumulates in the livers of these mice due to increased uridine Phosphorylase UPP2 activity. Furthermore, uracil-supplemented diet increases locomotion in wild-type mice. Thus, MIC19-induced mitochondrial cristae formation in the liver increases uracil as a signal to promote locomotion, with protective effects against diet-induced obesity.

Keywords

brisk walking; diabetes; fatty liver; mitochondrial cristae; obesity; uracil.

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