Kidney Stone Disease: Epigenetic Dysregulation in Homocystinuria and Mitochondrial Sulfur Trans-Sulfuration Ablation Driven by COVID-19 Pathophysiology

The aftermath of COVID-19, caused by the SARS-CoV-2 virus, has brought to light unexpected com-plications beyond the lungs including its connection to chronic kidney disease (CKD) and potentially, kidney stone disease (KSD). Kidney stones, classified as radiopaque or radiolucent, differ not only in composition but also in their biological origins. Radiopaque stones, which include calcium phosphate and oxalate types, are visible on X-rays, while radiolucent stones, such as uric acid and cystine, are not. Their formation is heavily influenced by urine pH: alkaline urine (pH ≥ 7) favors radiopaque stones, while acidic urine (pH ≤ 5.3) promotes radiolucent types. Because these stones stem from distinct molecular mechanisms, hence the “one size fits all” treatment approach has proven largely ineffective. Among the different categories of stones ranging from calcium-based to sulfur-containing types like those found in cystinuria or homocystinuria, the interplay of metabolic and epigenetic factors has been gaining attention. It appears that SARS-CoV-2 hijacks host methylation machinery, and by doing so leads to an increased production of homocysteine (Hcy), a non-protein amino acid that we believe is linked to stone formation. While cysteine can aid in calcium oxalate crystal aggregation, the elevated Hcy levels are often due to impaired mitochondrial sulfur metabolism (transsulfuration) that may be uniquely pathogenic in kidney stone development. Adding another layer of complexity, the COVID-19-associated gut dysbiosis, particularly involving Escherichia coli, can, in fact, de-grade citric acid (a key TCA cycle metabolite) into oxalic acid, thereby enhancing calcium oxalate stone formation. Moreover, SARS-CoV-2 induced succinylation of TCA cycle enzymes and disrupted mitochondrial bioenergetics further implicate defective transsulfuration as a bridge between acute kidney injury (AKI) and chronic stone disease. In essence, we opine that the COVID-19 may catalyze a shift from AKI to KSD through the host cell epigenetic reprogramming events, metabolic dysregulation, and mitochondrial sulfur pathway impairment revealing a novel link between viral infection, mitochondrial bioenergetics, and kidney stone pathogenesis.