Sex-specific genetic regulation of adipose mitochondria and metabolic syndrome by Ndufv2

Karthickeyan Chella Krishnan, Laurent Vergnes, Rebeca Acín-Pérez, Linsey Stiles, Michael Shum, Lijiang Ma, Etienne Mouisel, Calvin Pan, Timothy M. Moore, Miklós Péterfy, Casey E. Romanoski, Karen Reue, Johan L.M. Björkegren, Markku Laakso, Marc Liesa, Aldons J. Lusis

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


We have previously suggested a central role for mitochondria in the observed sex differences in metabolic traits. However, the mechanisms by which sex differences affect adipose mitochondrial function and metabolic syndrome are unclear. Here we show that in both mice and humans, adipose mitochondrial functions are elevated in females and are strongly associated with adiposity, insulin resistance and plasma lipids. Using a panel of diverse inbred strains of mice, we identify a genetic locus on mouse chromosome 17 that controls mitochondrial mass and function in adipose tissue in a sex- and tissue-specific manner. This locus contains Ndufv2 and regulates the expression of at least 89 mitochondrial genes in females, including oxidative phosphorylation genes and those related to mitochondrial DNA content. Overexpression studies indicate that Ndufv2 mediates these effects by regulating supercomplex assembly and elevating mitochondrial reactive oxygen species production, which generates a signal that increases mitochondrial biogenesis.

Original languageEnglish (US)
Pages (from-to)1552-1568
Number of pages17
JournalNature Metabolism
Issue number11
StatePublished - Nov 2021

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Cell Biology


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