Sex-Specific Genetic Regulation of Adipose Mitochondria and Their Relationship to Metabolic Syndrome
Karthickeyan Chella Krishnan1, Laurent Vergnes2, Linsey Stiles3, Lijiang Ma4, Rebeca Acín-Pérez3, Etienne Mouisel5, Calvin Pan1, Miklós Péterfy6, Karen Reue Vergnes2, Johan L.M. Björkegren4, Markku Laakso7, Aldons J. Lusis1,2,8
1Department of Medicine/Division of Cardiology, University of California, Los Angeles; 2Department of Human Genetics, University of California, Los Angeles; 3Department of Medicine/Division of Endocrinology, University of California, Los Angeles; 4Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai; 5INSERM, UMR1048, Institute of Metabolic and Cardiovascular Diseases, University of Toulouse; 6College of Osteopathic Medicine of the Pacific, Western University of Health Sciences; 7Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital; 8Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles.
Background and Objectives: Mitochondria plays a major role in the pathophysiology of complex metabolic traits such as obesity, insulin resistance and fatty liver disease. However, the exact causal relationship between mitochondrial function and these traits is not completely understood. Similarly, sex differences in susceptibility to metabolic phenotypes have been amply described in mice, humans and other species, with females generally exhibiting a beneficial metabolic profile. Yet, the vast majority of previous studies examined sex differences in phenotypes or gene expression in isolation, generating trait or tissue specific results without putting them in context of genetic variation. Methods: To understand the nature of the sex differences and causal relationships, we examined genetic factors contributing to mitochondrial function using a mouse reference population that were extensively phenotyped called hybrid mouse diversity panel. Results: We identified a genetic locus on mouse chromosome 17 that controls mitochondria levels and function in adipose tissue in a sex- and tissue-specific manner. It regulates the expression of at least 89 mitochondrial genes, many of them related to oxidative phosphorylation, as well as mitochondrial DNA levels, in female but not male mice. Overexpression studies indicate that the effects of the locus are mediated by the Ndufv2 gene that encodes a subunit of the mitochondrial complex-I. The gene is activated by gonadal hormones and is regulated in cis only in females. Conclusions: We report that adipose mitochondria are regulated by both genetic variation and sex hormones and that high levels are an important determinant of metabolic syndrome traits.
Breakout Room: Krishnan, Karthickeyan Chella
View Poster: https://uclacns.org/symposium2021/6-Krishnan-Karthickeyan-Chella.pdf