Cell Reports (Mar 2023)
Limiting Mrs2-dependent mitochondrial Mg2+ uptake induces metabolic programming in prolonged dietary stress
- Travis R. Madaris,
- Manigandan Venkatesan,
- Soumya Maity,
- Miriam C. Stein,
- Neelanjan Vishnu,
- Mridula K. Venkateswaran,
- James G. Davis,
- Karthik Ramachandran,
- Sukanthathulse Uthayabalan,
- Cristel Allen,
- Ayodeji Osidele,
- Kristen Stanley,
- Nicholas P. Bigham,
- Terry M. Bakewell,
- Melanie Narkunan,
- Amy Le,
- Varsha Karanam,
- Kang Li,
- Aum Mhapankar,
- Luke Norton,
- Jean Ross,
- M. Imran Aslam,
- W. Brian Reeves,
- Brij B. Singh,
- Jeffrey Caplan,
- Justin J. Wilson,
- Peter B. Stathopulos,
- Joseph A. Baur,
- Muniswamy Madesh
Affiliations
- Travis R. Madaris
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Manigandan Venkatesan
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Soumya Maity
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Miriam C. Stein
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Neelanjan Vishnu
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Mridula K. Venkateswaran
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- James G. Davis
- Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19103, USA
- Karthik Ramachandran
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Sukanthathulse Uthayabalan
- Department of Physiology and Pharmacology, Western University, London, ON N6A 5C1, Canada
- Cristel Allen
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Ayodeji Osidele
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Kristen Stanley
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Nicholas P. Bigham
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
- Terry M. Bakewell
- Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Melanie Narkunan
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Amy Le
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Varsha Karanam
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Kang Li
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Aum Mhapankar
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Luke Norton
- Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Jean Ross
- Department of Biological Sciences, Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USA
- M. Imran Aslam
- Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- W. Brian Reeves
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Brij B. Singh
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Jeffrey Caplan
- Department of Biological Sciences, Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USA
- Justin J. Wilson
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
- Peter B. Stathopulos
- Department of Physiology and Pharmacology, Western University, London, ON N6A 5C1, Canada
- Joseph A. Baur
- Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19103, USA; Corresponding author
- Muniswamy Madesh
- Department of Medicine, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Medicine, Cardiology/Diabetes Divisions, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 3
p. 112155
Abstract
Summary: The most abundant cellular divalent cations, Mg2+ (mM) and Ca2+ (nM-μM), antagonistically regulate divergent metabolic pathways with several orders of magnitude affinity preference, but the physiological significance of this competition remains elusive. In mice consuming a Western diet, genetic ablation of the mitochondrial Mg2+ channel Mrs2 prevents weight gain, enhances mitochondrial activity, decreases fat accumulation in the liver, and causes prominent browning of white adipose. Mrs2 deficiency restrains citrate efflux from the mitochondria, making it unavailable to support de novo lipogenesis. As citrate is an endogenous Mg2+ chelator, this may represent an adaptive response to a perceived deficit of the cation. Transcriptional profiling of liver and white adipose reveals higher expression of genes involved in glycolysis, β-oxidation, thermogenesis, and HIF-1α-targets, in Mrs2−/− mice that are further enhanced under Western-diet-associated metabolic stress. Thus, lowering mMg2+ promotes metabolism and dampens diet-induced obesity and metabolic syndrome.
