Architecture of Human Mitochondrial Respiratory Megacomplex I2III2IV2

Cell. 2017 Sep 7;170(6):1247-1257.e12. doi: 10.1016/j.cell.2017.07.050. Epub 2017 Aug 24.


The respiratory megacomplex represents the highest-order assembly of respiratory chain complexes, and it allows mitochondria to respond to energy-requiring conditions. To understand its architecture, we examined the human respiratory chain megacomplex-I2III2IV2 (MCI2III2IV2) with 140 subunits and a subset of associated cofactors using cryo-electron microscopy. The MCI2III2IV2 forms a circular structure with the dimeric CIII located in the center, where it is surrounded by two copies each of CI and CIV. Two cytochrome c (Cyt.c) molecules are positioned to accept electrons on the surface of the c1 state CIII dimer. Analyses indicate that CII could insert into the gaps between CI and CIV to form a closed ring, which we termed the electron transport chain supercomplex. The structure not only reveals the precise assignment of individual subunits of human CI and CIII, but also enables future in-depth analysis of the electron transport chain as a whole.

Keywords: cryo-EM; electron transfer pathway; human respiratory chain; megacomplex; mitochondria; oxidative phosphorylation.

MeSH terms

  • Cryoelectron Microscopy
  • Electron Transport Chain Complex Proteins / chemistry*
  • Electron Transport Chain Complex Proteins / isolation & purification
  • Electron Transport Chain Complex Proteins / metabolism
  • Electron Transport Complex I / chemistry
  • Electron Transport Complex I / isolation & purification
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex II / chemistry
  • Electron Transport Complex II / isolation & purification
  • Electron Transport Complex II / metabolism
  • Humans
  • Mitochondria / chemistry
  • Mitochondria / metabolism
  • Models, Molecular
  • Multienzyme Complexes / chemistry*
  • Multienzyme Complexes / isolation & purification
  • Multienzyme Complexes / metabolism


  • Electron Transport Chain Complex Proteins
  • Multienzyme Complexes
  • respiratory complex II
  • Electron Transport Complex II
  • Electron Transport Complex I