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.
Eduardo Balsa  1 ,  Meghan S Soustek  1 ,  Ajith Thomas  1 ,  Sara Cogliati  2 ,  Carolina García-Poyatos  2 ,  Elena Martín-García  2 ,  Mark Jedrychowski  3 ,  Steve P Gygi  3 ,  José Antonio Enriquez  4 ,  Pere Puigserver  5
Affiliations
  • 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 2. Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029 Madrid, Spain.
  • 3. Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 4. Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029 Madrid, Spain; CIBERFES, Institute of Health Carlos III, Madrid 28029, Spain.
  • 5. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 31023583 DOI: 10.1016/j.molcel.2019.03.031
Abstract

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.