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Limiting Mrs2-dependent mitochondrial Mg²⁺ uptake induces metabolic programming in prolonged dietary stress.

ABSTRACT: 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.

SUBMITTER: Madaris TR

PROVIDER: S-EPMC10134742 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Limiting Mrs2-dependent mitochondrial Mg2+ uptake induces metabolic programming in prolonged dietary stress.

Madaris Travis R TR Venkatesan Manigandan M Maity Soumya S Stein Miriam C MC Vishnu Neelanjan N Venkateswaran Mridula K MK Davis James G JG Ramachandran Karthik K Uthayabalan Sukanthathulse S Allen Cristel C Osidele Ayodeji A Stanley Kristen K Bigham Nicholas P NP Bakewell Terry M TM Narkunan Melanie M Le Amy A Karanam Varsha V Li Kang K Mhapankar Aum A Norton Luke L Ross Jean J Aslam M Imran MI Reeves W Brian WB Singh Brij B BB Caplan Jeffrey J Wilson Justin J JJ Stathopulos Peter B PB Baur Joseph A JA Madesh Muniswamy M

Cell reports 20230227 3

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 browni ...[more]

PMID: 36857182

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Project description:N-linked glycoproteins function in numerous biological processes, modulating enzyme activities as well as protein folding, stability, oligomerization, and trafficking. While N-glycosylation of mitochondrial proteins has been detected by untargeted MS-analyses, the physiological existence and roles of mitochondrial protein N-linked glycosylation remain under debate. Here, we report that MRS2, a mitochondrial inner membrane protein that functions as the high flux magnesium transporter, is N-glycosylated to various extents depending on cellular bioenergetic status. Both N-glycosylated and unglycosylated isoforms were consistently detected in mitochondria isolated from mouse liver, rat and mouse liver fibroblast cells (BRL 3A and AFT024, respectively) as well as human skin fibroblast cells. Immunoblotting of MRS2 showed it was bound to, and required stringent elution conditions to remove from, lectin affinity columns with covalently bound concanavalin A or Lens culinaris agglutinin. Following peptide:N-glycosidase F (PNGase F) digestion of the stringently eluted proteins, the higher Mr MRS2 bands gel-shifted to lower Mr and loss of lectin affinity was seen. BRL 3A cells treated with two different N-linked glycosylation inhibitors, tunicamycin or 6-diazo-5-oxo-l-norleucine, resulted in decreased intensity or loss of the higher Mr MRS2 isoform. To investigate the possible functional role of MRS2 N- glycosylation, we measured rapid Mg2+ influx capacity in intact mitochondria isolated from BRL 3A cells in control media or following treatment with tunicamycin or 6-diazo-5-oxo-l-norleucine. Interestingly, rapid Mg2+ influx capacity increased in mitochondria isolated from BRL 3A cells treated with either N-glycosylation inhibitor. Forcing reliance on mitochondrial respiration by treatment with either galactose media or the glycolytic inhibitor 2-deoxyglucose or by minimizing glucose concentration similarly reduced the N-glycosylated isoform of MRS2, with a correlated concomitant increase in rapid Mg2+ influx capacity. Conversely, inhibiting mitochondrial energy production in BRL 3A cells with either rotenone or oligomycin resulted in an increased fraction of N-glycosylated MRS2, with decreased rapid Mg2+ influx capacity. Collectively, these data provide strong evidence that MRS2 N-glycosylation is directly involved in the regulation of mitochondrial matrix Mg2+, dynamically communicating relative cellular nutrient status and bioenergetic capacity by serving as a physiologic brake on the influx of mitochondrial matrix Mg2+ under conditions of glucose excess or mitochondrial bioenergetic impairment.

Dataset Information

Limiting Mrs2-dependent mitochondrial Mg²⁺ uptake induces metabolic programming in prolonged dietary stress.

Publications

Limiting Mrs2-dependent mitochondrial Mg<sup>2+</sup> uptake induces metabolic programming in prolonged dietary stress.

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