Endoplasmic reticulum-associated degradation regulates mitochondrial dynamics in brown adipocytes

Science. 2020 Apr 3;368(6486):54-60. doi: 10.1126/science.aay2494. Epub 2020 Mar 19.

Abstract

The endoplasmic reticulum (ER) engages mitochondria at specialized ER domains known as mitochondria-associated membranes (MAMs). Here, we used three-dimensional high-resolution imaging to investigate the formation of pleomorphic "megamitochondria" with altered MAMs in brown adipocytes lacking the Sel1L-Hrd1 protein complex of ER-associated protein degradation (ERAD). Mice with ERAD deficiency in brown adipocytes were cold sensitive and exhibited mitochondrial dysfunction. ERAD deficiency affected ER-mitochondria contacts and mitochondrial dynamics, at least in part, by regulating the turnover of the MAM protein, sigma receptor 1 (SigmaR1). Thus, our study provides molecular insights into ER-mitochondrial cross-talk and expands our understanding of the physiological importance of Sel1L-Hrd1 ERAD.

Publication types

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

MeSH terms

  • Adipocytes, Brown / metabolism
  • Adipocytes, Brown / physiology*
  • Animals
  • Cold Temperature
  • Endoplasmic Reticulum Stress / genetics
  • Endoplasmic Reticulum Stress / physiology*
  • Endoplasmic Reticulum-Associated Degradation / genetics
  • Endoplasmic Reticulum-Associated Degradation / physiology*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Mutant Strains
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Mitochondrial Dynamics*
  • Mitochondrial Membranes / metabolism
  • Receptors, sigma / metabolism
  • Thermogenesis / genetics
  • Thermogenesis / physiology*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Intracellular Signaling Peptides and Proteins
  • Receptors, sigma
  • Sel1h protein, mouse
  • sigma-1 receptor
  • Syvn1 protein, mouse
  • Ubiquitin-Protein Ligases