Peroxisomal-derived ether phospholipids link nucleotides to respirasome assembly

Nat Chem Biol. 2021 Jun;17(6):703-710. doi: 10.1038/s41589-021-00772-z. Epub 2021 Mar 15.


The protein complexes of the mitochondrial electron transport chain exist in isolation and in higher order assemblies termed supercomplexes (SCs) or respirasomes (SC I+III2+IV). The association of complexes I, III and IV into the respirasome is regulated by unknown mechanisms. Here, we designed a nanoluciferase complementation reporter for complex III and IV proximity to determine in vivo respirasome levels. In a chemical screen, we found that inhibitors of the de novo pyrimidine synthesis enzyme dihydroorotate dehydrogenase (DHODH) potently increased respirasome assembly and activity. By-passing DHODH inhibition via uridine supplementation decreases SC assembly by altering mitochondrial phospholipid composition, specifically elevated peroxisomal-derived ether phospholipids. Cell growth rates upon DHODH inhibition depend on ether lipid synthesis and SC assembly. These data reveal that nucleotide pools signal to peroxisomes to modulate synthesis and transport of ether phospholipids to mitochondria for SC assembly, which are necessary for optimal cell growth in conditions of nucleotide limitation.

Publication types

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

MeSH terms

  • Dihydroorotate Dehydrogenase
  • Electron Transport Complex III / genetics
  • Electron Transport Complex IV / genetics
  • Electron Transport* / genetics
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Lipids / biosynthesis
  • Metabolomics
  • Mitochondria / metabolism
  • Molecular Structure
  • Nucleotides / chemistry*
  • Oxidoreductases Acting on CH-CH Group Donors / chemistry
  • Oxygen Consumption
  • Peroxisomes / chemistry*
  • Phospholipid Ethers
  • Phospholipids / chemistry*
  • Uridine / metabolism


  • Dihydroorotate Dehydrogenase
  • Lipids
  • Nucleotides
  • Phospholipid Ethers
  • Phospholipids
  • Oxidoreductases Acting on CH-CH Group Donors
  • Electron Transport Complex IV
  • Electron Transport Complex III
  • Uridine