Long COVID: The roles of magnesium and angiotensin-converting enzyme 2

The functions of magnesium (Mg) and angiotensin-converting enzyme 2 (ACE2) in lowering blood pressure are well known; however, their roles in long COVID (LC) remain unclear. This review proposes a hypothetical model that mechanistically links symptoms of LC to: (i) deficiencies in essential ACE2-dependent neutral amino acids, including tryptophan and methionine; (ii) altered Mg-dependent one-carbon metabolism; (iii) altered Mg-dependent autophagy; and (iv) altered Mg-dependent mechanistic target of rapamycin (mTOR) signaling, potentially modulated by rapamycin. Mg and vitamin D deficiency are linked to LC. All forms of vitamin D, including its cutaneous precursor, are Mg-dependent. Accordingly, Mg is proposed as an essential factor in the prevention and/or attenuation of LC. The SARS-CoV-2 virus targets ACE2-expressing cells, leading to the downregulation of ACE2 function. ACE2 and sodium-dependent neutral amino acid transporter are required for the absorption of tryptophan, methionine, and branched-chain amino acids, all of which are low in LC. Loss of ACE2 negatively impacts the Mg-dependent serotonin pathway, the Mg-dependent indole pathway, and the methionine-dependent one-carbon metabolism. Autophagy and mTOR kinase are Mg-dependent. Additionally, individuals carrying the methylenetetrahydrofolate reductase 677T allele—which is prevalent in many populations—may exhibit further impairment in one-carbon metabolism. Gut dysbiosis, present in almost 75% of long haulers, may enable Candida overgrowth. Candidalysin has been shown to upregulate mTOR and inhibit autophagy, similar to mechanisms employed by several viruses, including SARS-CoV-2, and may contribute to chronic fatigue. Although numerous linkages are outlined, this mechanistic model is hypothetical, and causal relationships require validation through clinical studies.