Limiting Mrs2-dependent mitochondrial Mg2+ uptake induces metabolic programming in prolonged dietary stress , 2023, Madaris

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.

https://www.cell.com/cell-reports/f...m/retrieve/pii/S2211124723001663?showall=true

 

So, nothing ME/CFS here. And the chemistry is far beyond my understanding.
However, there are a few reasons this seems important to me:
1) new understanding of the role of mitochondrial magnesium;
2) and its relationship to calcium;
3) intracellular Ca overload plays a significant role in the ME/CFS hypotheses of Wirth and Scheibenbogen;
4) in this study, restricting mito Mg leads to increased glucose and lipid metabolism, both of which have been reported to be restricted in ME/CFS;
5) yet Mg supplementation is reported to improve some ME/CFS symptoms (although, of course, serum Mg does not equal intracellular Mg does not equal mito Mg).
I don't understand fatigue. I assume it's a signalling issue in ME/CFS, rather than a dearth of intracellular ATP, but altered substrate metabolism appears to be part of its phenotype. Perhaps this paper will add to our understanding of that. (Well, it will add to *your* understanding of it - I'm too dense.)