Cell Rep. 2026 Oct 20;45(11):118166. doi: 10.1016/j.celrep.2026.118166. Online ahead of print.
ABSTRACT
Endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR) to enhance metabolism and restore homeostasis by increasing mitochondrial calcium at mitochondrial-endoplasmic reticulum contact sites (MERCs). Unresolved ER stress is deleterious and contributes to the severity of diseases such as myocardial infarction (MI). The identity of the MERC calcium source and its interplay with the UPR is unclear. We find that ER-localized polycystin-2 (PC2), a calcium channel, is upregulated in cardiomyocytes with MI. Cardiomyocyte PC2-knockout mice with MI exhibit worsened heart function and decreased PERK. ER stress induces a PC2-facilitated adaptive ER calcium leak and PC2 localization to MERCs. PC2 requires PERK phosphorylation for mitochondrial calcium transfer. PC2 mutations impair ER calcium leak, restored by full-length PC2 expression. Thus, PC2 functions in a PERK-dependent manner under ER stress to provide mitochondrial calcium, and its upregulation is cardioprotective in MI.
PMID:42900588 | DOI:10.1016/j.celrep.2026.118166