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

Mol Cell. 2019 Jun 6;74(5):877-890.e6. doi: 10.1016/j.molcel.2019.03.031. Epub 2019 Apr 22.


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.

Keywords: ATF4; ER stress; PERK; hexosamine pathway; mitochondria; mitochondrial cristae; mitochondrial diseases; nutrient stress; protein glycosylation; respiratory chain supercomplexes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / genetics*
  • Adenosine Triphosphate / metabolism
  • Animals
  • Apoptosis
  • Cell Line
  • Cell Survival / genetics
  • Electron Transport Complex I / genetics
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex IV / genetics
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress / genetics
  • Energy Metabolism / genetics*
  • Eukaryotic Initiation Factor-2 / genetics*
  • Glucose / metabolism
  • Humans
  • Mice
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Diseases / pathology
  • Mutation, Missense / genetics
  • Nutrients / metabolism
  • Phosphorylation
  • Serine-Arginine Splicing Factors / genetics
  • Signal Transduction
  • eIF-2 Kinase / genetics*


  • ATF4 protein, human
  • COX7A2L protein, human
  • Eukaryotic Initiation Factor-2
  • SCAF1 protein, human
  • Activating Transcription Factor 4
  • Serine-Arginine Splicing Factors
  • Adenosine Triphosphate
  • Electron Transport Complex IV
  • EIF2AK3 protein, human
  • eIF-2 Kinase
  • Electron Transport Complex I
  • Glucose