A membrane arm of mitochondrial complex I sufficient to promote respirasome formation

Cell Rep. 2021 Apr 13;35(2):108963. doi: 10.1016/j.celrep.2021.108963.

Abstract

The assembly pathways of mitochondrial respirasome (supercomplex I+III2+IV) are not fully understood. Here, we show that an early sub-complex I assembly, rather than holo-complex I, is sufficient to initiate mitochondrial respirasome assembly. We find that a distal part of the membrane arm of complex I (PD-a module) is a scaffold for the incorporation of complexes III and IV to form a respirasome subcomplex. Depletion of PD-a, rather than other complex I modules, decreases the steady-state levels of complexes III and IV. Both HEK293T cells lacking TIMMDC1 and patient-derived cells with disease-causing mutations in TIMMDC1 showed accumulation of this respirasome subcomplex. This suggests that TIMMDC1, previously known as a complex-I assembly factor, may function as a respirasome assembly factor. Collectively, we provide a detailed, cooperative assembly model in which most complex-I subunits are added to the respirasome subcomplex in the lateral stages of respirasome assembly.

Keywords: Leigh syndrome; TIMMDC1; cooperative assembly; mitochondrial respirasome; oxidative phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes
  • Cell Line, Transformed
  • Developmental Disabilities / genetics
  • Developmental Disabilities / metabolism
  • Developmental Disabilities / pathology
  • Electron Transport Complex I / antagonists & inhibitors
  • Electron Transport Complex I / genetics*
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex III / antagonists & inhibitors
  • Electron Transport Complex III / genetics*
  • Electron Transport Complex III / metabolism
  • Electron Transport Complex IV / antagonists & inhibitors
  • Electron Transport Complex IV / genetics*
  • Electron Transport Complex IV / metabolism
  • Embryo, Nonmammalian
  • Gene Expression Regulation, Developmental
  • HEK293 Cells
  • Humans
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Precursor Protein Import Complex Proteins / deficiency
  • Mitochondrial Precursor Protein Import Complex Proteins / genetics*
  • Morpholinos / genetics
  • Morpholinos / metabolism
  • Muscle Hypotonia / genetics
  • Muscle Hypotonia / metabolism
  • Muscle Hypotonia / pathology
  • Oxidative Phosphorylation
  • Zebrafish

Substances

  • Mitochondrial Precursor Protein Import Complex Proteins
  • Morpholinos
  • TIMMDC1 protein, human
  • Electron Transport Complex IV
  • Electron Transport Complex I
  • Electron Transport Complex III