PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are linked in the onset and pathogenesis of numerous diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria during ER stress. The PERK signaling arm of the unfolded protein response (UPR) has emerged as a prominent ER stress‐responsive signaling pathway that regulates diverse aspects of mitochondrial biology. Here, we show that PERK activity promotes adaptive remodeling of mitochondrial membrane phosphatidic acid (PA) to induce protective mitochondrial elongation during acute ER stress. We find that PERK activity is required for ER stress‐dependent increases in both cellular PA and YME1L‐dependent degradation of the intramitochondrial PA transporter PRELID1. These two processes lead to the accumulation of PA on the outer mitochondrial membrane where it can induce mitochondrial elongation by inhibiting mitochondrial fission. Our results establish a new role for PERK in the adaptive remodeling of mitochondrial phospholipids and demonstrate that PERK‐dependent PA regulation adapts organellar shape in response to ER stress. Synopsis The PERK arm of the unfolded protein response (UPR) promotes adaptive mitochondrial elongation in response to acute endoplasmic reticulum (ER) stress. Here, we show that PERK‐dependent mitochondrial elongation is induced through a mechanism involving the remodeling of phosphatidic acid (PA) within mitochondrial membranes. Hypomorphic, disease‐associated PERK variants impair ER stress‐induced mitochondrial elongation. Active PERK increases cellular phosphatidic acid (PA) in response to acute ER stress. The intramitochondrial PA transporter PRELID1 is decreased downstream of PERK activation. PERK promotes PA accumulation on the outer mitochondrial membrane where it inhibits mitochondrial fission. Graphical Abstract PERK regulates the composition of mitochondrial phospholipids, thus adapting their morphology to ER stress.