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

Jee Hyung Sohn, Beste Mutlu, Pedro Latorre-Muro, Jiaxin Liang, Christopher F. Bennett, Kfir Sharabi, Noa Kantorovich, Mark Jedrychowski, Steven P. Gygi, Alexander S. Banks, Pere Puigserver*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageAmerican English
Pages (from-to)1356-1372.e5
JournalCell Metabolism
Volume35
Issue number8
DOIs
StatePublished - 8 Aug 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Inc.

Keywords

  • brisk walking
  • diabetes
  • fatty liver
  • mitochondrial cristae
  • obesity
  • uracil

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