Mitochondrial calcium efflux drives ferroptosis via the CaMKII/HIF-1α/TFRC axis in cadmium-induced proximal tubular injury

Cadmium (Cd) exposure triggers ferroptosis in renal tubular cells. • TFRC upregulation drives Cd‑induced ferroptosis by promoting iron influx. • HIF‑1α directly binds the TFRC promoter to transactivate its expression. • mPTP‑mediated calcium efflux activates CaMKII/HIF‑1α/TFRC axis. Cadmium (Cd) is a ubiquitous environmental pollutant and well-established nephrotoxicant primarily targeting renal proximal tubular cells. Ferroptosis, an iron‑dependent form of regulated cell death driven by lipid peroxidation, has recently emerged as a key mechanism in Cd‑induced kidney injury. Despite the central role of mitochondria in ferroptosis, the precise organellar events linking Cd exposure to ferroptotic execution remain obscure. Using Sprague‑Dawley rats and renal proximal tubular cells, we found that Cd exposure instigated ferroptosis, evidenced by iron overload, altered ferroptosis markers, lipid peroxidation, and typical mitochondrial morphology under transmission electron microscopy. Pharmacological inhibition of ferroptosis significantly attenuated Cd‑induced cellular damage, identifying ferroptosis as a critical driver. Mechanistically, Cd triggered opening of the mitochondrial permeability transition pore (mPTP), leading to mitochondrial calcium efflux and activation of calcium/calmodulin‑dependent protein kinase II (CaMKII). Activated CaMKII in turn increased hypoxia-inducible factor-1α (HIF-1α) transcription and promoted its nuclear accumulation. Notably, upregulated HIF‑1α directly bound to the promoter of transferrin receptor (TFRC) to stimulate expression of this key iron transport mediator, as confirmed by chromatin immunoprecipitation assay. Moreover, genetic knockdown of TFRC markedly attenuated Cd‑triggered ferroptosis and consequent cytotoxicity, establishing TFRC as a critical executioner of Cd‑evoked renal injury. Taken together, these findings delineate a novel signaling axis from mPTP‑mediated calcium efflux to HIF‑1α‑dependent TFRC transactivation that drives ferroptosis in Cd‑induced nephrotoxicity, offering a mechanistic basis for understanding and mitigating the renal health risks posed by environmental Cd exposure. Download: Download high-res image (405KB) Download: Download full-size image