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ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2α Axis

Endoplasmic reticulum (ER) stress and unfolded protein response are energetically challenging under nutrient stress conditions. However, the regulatory mechanisms that control the energetic demand under nutrient and ER stress are largely unknown. Here we show that ER stress and glucose deprivation s...

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Bibliographic Details
Published in:Molecular cell 2019-06, Vol.74 (5), p.877-890.e6
Main Authors: Balsa, Eduardo, Soustek, Meghan S., Thomas, Ajith, Cogliati, Sara, García-Poyatos, Carolina, Martín-García, Elena, Jedrychowski, Mark, Gygi, Steve P., Enriquez, José Antonio, Puigserver, Pere
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Language:English
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Summary:Endoplasmic reticulum (ER) stress and unfolded protein response are energetically challenging under nutrient stress conditions. However, the regulatory mechanisms that control the energetic demand under nutrient and ER stress are largely unknown. Here we show that ER stress and glucose deprivation stimulate mitochondrial bioenergetics and formation of respiratory supercomplexes (SCs) through protein kinase R-like ER kinase (PERK). Genetic ablation or pharmacological inhibition of PERK suppresses nutrient and ER stress-mediated increases in SC levels and reduces oxidative phosphorylation-dependent ATP production. Conversely, PERK activation augments respiratory SCs. The PERK-eIF2α-ATF4 axis increases supercomplex assembly factor 1 (SCAF1 or COX7A2L), promoting SCs and enhanced mitochondrial respiration. PERK activation is sufficient to rescue bioenergetic defects caused by complex I missense mutations derived from mitochondrial disease patients. These studies have identified an energetic communication between ER and mitochondria, with implications in cell survival and diseases associated with mitochondrial failures. [Display omitted] •ER and nutrient stress increase mitochondrial oxidative phosphorylation•PERK increases formation of mitochondrial cristae and respiratory supercomplexes•PERK-ATF4 promotes assembly of respiratory supercomplexes through SCAF1•PERK activation rescues bioenergetic failures in human complex I mutant cells ER and nutrient stress cause mitochondrial energetic demands to maintain cell survival that can be compromised in diseases associated with mitochondrial failures. Balsa et al. use a series of metabolic and proteomic analyses to identify the ER and nutrient stress-activated PERK that promotes formation of respiratory supercomplexes through the assembly factor SCAF1.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2019.03.031