Ergothioneine and Renal Mitochondrial Protection: OCTN1-Mediated Accumulation in Proximal Tubular Cells as a Parallel and Non-Redundant Antioxidant Defense Alongside GPx3 in the Selenoprotein Axis Framework

This paper proposes that ergothioneine represents a parallel and non-redundant mitochondrial antioxidant defense mechanism in renal proximal tubular cells alongside GPx3 — one that is selenium-independent but functionally complementary. Ergothioneine protects mitochondria through direct metal chelation, hydroxyl radical scavenging, peroxynitrite neutralization, and mitochondrial membrane stabilization — mechanisms that GPx3-mediated hydrogen peroxide reduction does not cover. OCTN1 knockout mice show worse diabetic nephropathy, ischemic kidney injury, and oxidative fibrosis through a GPx3-independent mechanism. A 2025 NIH study confirmed ergothioneine is markedly depleted in hemodialysis patients. The dual depletion of both independent renal antioxidant systems (GPx3 and ergothioneine-OCTN1) in end-stage CKD patients has not been previously recognized as a compounding clinical factor. All claims are hypothesis-level.