When calcium crosstalk turns ferroptotic: the SERCA2-VDAC1 axis in AKI.

Hong, Yu Ah · Kidney Int · 2026

basic_science · Level V

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Abstract

Organelle communication through endoplasmic reticulum-mitochondrial crosstalk is essential for maintaining cellular homeostasis and is tightly regulated by tethering proteins within mitochondria-associated endoplasmic reticulum membranes. In a recent study published in Kidney International, He et al. identified sarcoplasmic/endoplasmic reticulum Ca<sup>2+</sup>-ATPase 2 as a key regulator of endoplasmic reticulum-mitochondrial calcium homeostasis in proximal tubules and demonstrated that loss of sarcoplasmic/endoplasmic reticulum Ca<sup>2+</sup>-ATPase 2 drives voltage-dependent anion channel 1 oligomerization, mitochondrial DNA release, stimulator of interferon genes activation, and ferroptosis in acute kidney injury. This study establishes the sarcoplasmic/endoplasmic reticulum Ca<sup>2+</sup>-ATPase 2-voltage-dependent anion channel 1 axis as a mechanistic link between mitochondrial calcium dysregulation and ferroptotic tubular injury.

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