PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid

Abstract

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.

Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations

“…Consistent with this, ISR activation has been shown to regulate diverse aspects of mitochondrial biology including proteostasis, morphology, energy metabolism, lipid metabolism, and apoptotic signaling. [15][16][17][18][19][20][21][22][23][24] Thus, combined recent results demonstrating both a signaling mechanism to activate the ISR in response to mitochondrial stress and an adaptive program to promote mitochondrial remodeling following pathologic insults highlights a central role for the ISR in regulating mitochondria in response to stress. Our work further highlights the central importance of the ISR for mitochondrial regulation, identifying the ISR as the only stress responsive signaling pathway activated by perturbations to mitochondrial proteostasis and function.…”

“…18,19 ISR signaling has also been implicated in the regulation of many other aspects of mitochondrial biology including energy metabolism, lipid regulation, and organellar morphology. 18,[20][21][22][23][24] These results highlight a central role for the ISR in regulating mitochondria in response to stress.…”

“…18,19 ISR signaling has also been implicated in the regulation of many other aspects of mitochondrial biology including energy metabolism, lipid regulation, and organellar morphology. 18,[20][21][22][23][24] These results highlight a central role for the ISR in regulating mitochondria in response to stress.Recent work has revealed the molecular mechanism by which mitochondrial stress activates ISR signaling. In response to mitochondrial stress, the stress-sensing mitochondrial protein DELE1 accumulates in…”

UBXN1 maintains ER proteostasis and represses UPR activation by modulating translation

“…In parallel, the PERK-peIF2α pathway also promotes ER stress-induced mitochondrial hyperfusion (SIMH) (Lebeau et al, 2018 ; Adachi et al, 2016 ; Bobrovnikova-Marjon et al, 2012 ; Perea et al, 2023 ). SIMH aids in cellular recovery after ER stress by preventing premature mitochondrial fragmentation, thereby enhancing the activity of the electron transport chain (Lebeau et al, 2018 ; Adachi et al, 2016 ; Bobrovnikova-Marjon et al, 2012 ; Perea et al, 2023 ). We evaluated mitochondrial morphology by immunofluorescence of TOMM20 in wild-type and UBXN1 KO cells treated with ER stress.…”

Optogenetic strategies for optimizing the performance of biosensors of membrane phospholipids in live cells

“…4C), further suggesting a low basal level of PA on the mitochondrial membrane. Increasing PA has been implicated in mitochondrial dynamics and mitophagy [34][35][36][37] and addressing its spatiotemporal regulatory mechanisms required high-performance biosensor. To elevate the PA level on the mitochondria, we overexpressed mitochondria-localized PLD PMF100× , resulting in substantial puncta located on the outer membrane of mitochondria as detected by both GPF-fused and mCh-fused Opto-PASSps biosensor (Fig.…”