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

doi:10.1038/s42255-021-00481-w

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

Nat Metab. 2021 Nov;3(11):1552-1568. doi: 10.1038/s42255-021-00481-w. Epub 2021 Oct 25.

Authors

Karthickeyan Chella Krishnan^{1

2}, Laurent Vergnes^#³, Rebeca Acín-Pérez^#⁴, Linsey Stiles^{4

5}, Michael Shum^{4

6}, Lijiang Ma⁷, Etienne Mouisel⁸, Calvin Pan³, Timothy M Moore⁹, Miklós Péterfy^{9

10}, Casey E Romanoski¹¹, Karen Reue³, Johan L M Björkegren^{7

12}, Markku Laakso¹³, Marc Liesa^{4

5}, Aldons J Lusis^{14

15

16}

Affiliations

¹ Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA. chellakn@ucmail.uc.edu.
² Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA. chellakn@ucmail.uc.edu.
³ Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Medicine/Division of Endocrinology, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Department of Molecular Medicine, Faculty of Medicine, Universite Laval, Quebec City, Quebec, Canada.
⁷ Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ INSERM, UMR1297, Institute of Metabolic and Cardiovascular Diseases, University of Toulouse, Paul Sabatier University, Toulouse, France.
⁹ Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA.
¹⁰ College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, USA.
¹¹ Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA.
¹² Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden.
¹³ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
¹⁴ Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA. jlusis@mednet.ucla.edu.
¹⁵ Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA. jlusis@mednet.ucla.edu.
¹⁶ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA. jlusis@mednet.ucla.edu.

^# Contributed equally.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue / metabolism*
Adiposity / genetics
Animals
Biomarkers*
Cell Respiration / genetics
Chromosomes, Human, Pair 17
Disease Models, Animal
Disease Susceptibility
Female
Gene Expression Profiling
Gene Expression Regulation*
Genetic Association Studies
Humans
Male
Metabolic Syndrome / diagnosis
Metabolic Syndrome / etiology*
Metabolic Syndrome / metabolism*
Mice
Mitochondria / genetics*
Mitochondria / metabolism*
NADH Dehydrogenase / genetics*
NADH Dehydrogenase / metabolism
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Quantitative Trait, Heritable
Reactive Oxygen Species / metabolism
Sex Factors

Substances

Biomarkers
Reactive Oxygen Species
NADH Dehydrogenase
NDUFV2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding