Limiting Mrs2-dependent mitochondrial Mg2+ uptake induces metabolic programming in prolonged dietary stress
| Author(s) | Madaris, Travis R. | |
| Author(s) | Venkatesan, Manigandan | |
| Author(s) | Maity, Soumya | |
| Author(s) | Stein, Miriam C. | |
| Author(s) | Vishnu, Neelanjan | |
| Author(s) | Venkateswaran, Mridula K. | |
| Author(s) | Davis, James G. | |
| Author(s) | Ramachandran, Karthik | |
| Author(s) | Uthayabalan, Sukanthathulse | |
| Author(s) | Allen, Cristel | |
| Author(s) | Osidele, Ayodeji | |
| Author(s) | Stanley, Kristen | |
| Author(s) | Bigham, Nicholas P. | |
| Author(s) | Bakewell, Terry M. | |
| Author(s) | Narkunan, Melanie | |
| Author(s) | Le, Amy | |
| Author(s) | Karanam, Varsha | |
| Author(s) | Li, Kang | |
| Author(s) | Mhapankar, Aum | |
| Author(s) | Norton, Luke | |
| Author(s) | Ross, Jean | |
| Author(s) | Aslam, M. Imran | |
| Author(s) | Reeves, W. Brian | |
| Author(s) | Singh, Brij B. | |
| Author(s) | Caplan, Jeffrey | |
| Author(s) | Wilson, Justin J. | |
| Author(s) | Stathopulos, Peter B. | |
| Author(s) | Baur, Joseph A. | |
| Author(s) | Madesh, Muniswamy | |
| Date Accessioned | 2023-05-01T20:11:09Z | |
| Date Available | 2023-05-01T20:11:09Z | |
| Publication Date | 2023-03-28 | |
| Description | This article was originally published in Cell Reports. The version of record is available at: https://doi.org/10.1016/j.celrep.2023.112155 | |
| Abstract | Highlights: • Mitochondrial Mg2+ channel Mrs2 rheostats MCU Ca2+ signals to maintain bioenergetic circuit • DNL precursor and cellular Mg2+ chelator citrate curbs HIF1α signal and oxidative metabolism • Lowering mMg2+ mitigates prolonged dietary-stress-induced obesity and metabolic syndrome • Mrs2 channel blocker CPACC reduces lipid accumulation and promotes browning and weight loss 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. Graphical abstract Available at: https://doi.org/10.1016/j.celrep.2023.112155 | |
| Sponsor | We thank Robert Campbell and William G. Kaelin Jr for sharing the cyto-Citron1 (addgene#134303) and mito-Citron1 (addgene#134305) plasmids and HIF1-α mutant (addgene#87261) constructs. We also thank the Department of Pathology and Laboratory Medicine histology core facility at UTHSA for histology preparation/staining. This research was funded by the National Institutes of Health (R35GM145294, R01GM109882, R01DK135179, and R01HL142673) to M.M. This work was partly supported by DOD/DHP-CDMRP PR181598P-1 and San Antonio Partnership for Precision Therapeutics (SAPPT) to M.M., CIHR-438225 to P.B.S., and National Science Foundation (CHE-1750295) to J.J.W. T.R.M. is supported by the NIH (R01GM109882-S1 and T32 AG 021890). We thank the Rodent Metabolic Phenotyping Core, supported in part by the Penn Diabetes Research Center grant (P30-DK19525) and S10-OD025098. Declaration of interests M.M. is an inventor on a patent filed by UTHSA on CPACC as a Mrs2 blocker for Mg2+ in physiology and disease. J.A.B. is a consultant to Pfizer. | |
| Citation | Madaris, Travis R., Manigandan Venkatesan, Soumya Maity, Miriam C. Stein, Neelanjan Vishnu, Mridula K. Venkateswaran, James G. Davis, et al. “Limiting Mrs2-Dependent Mitochondrial Mg2+ Uptake Induces Metabolic Programming in Prolonged Dietary Stress.” Cell Reports 42, no. 3 (March 28, 2023): 112155. https://doi.org/10.1016/j.celrep.2023.112155. | |
| ISSN | 2211-1247 | |
| URL | https://udspace.udel.edu/handle/19716/32695 | |
| Language | en_US | |
| Publisher | Cell Reports | |
| Keywords | magnesium channel | |
| Keywords | calcium channel | |
| Keywords | MCU | |
| Keywords | Mrs2 | |
| Keywords | energy imbalance | |
| Keywords | whole-body metabolism | |
| Keywords | mitochondrial dysfunction | |
| Keywords | liver | |
| Keywords | metabolic syndrome | |
| Keywords | NAFLD | |
| Keywords | obesity | |
| Keywords | HCC | |
| Keywords | adipose tissue | |
| Keywords | cardiometabolic disease | |
| Keywords | hepatocytes | |
| Keywords | adipose expansion | |
| Keywords | Western diet | |
| Keywords | diabetes | |
| Keywords | metabolic disease | |
| Keywords | HIF1 | |
| Title | Limiting Mrs2-dependent mitochondrial Mg2+ uptake induces metabolic programming in prolonged dietary stress | |
| Type | Article |
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