Mitochondrial disorders of the OXPHOS system

FEBS Lett. 2021 Apr;595(8):1062-1106. doi: 10.1002/1873-3468.13995. Epub 2020 Dec 18.


Mitochondrial disorders are among the most frequent inborn errors of metabolism, their primary cause being the dysfunction of the oxidative phosphorylation system (OXPHOS). OXPHOS is composed of the electron transport chain (ETC), formed by four multimeric enzymes and two mobile electron carriers, plus an ATP synthase [also called complex V (cV)]. The ETC performs the redox reactions involved in cellular respiration while generating the proton motive force used by cV to synthesize ATP. OXPHOS biogenesis involves multiple steps, starting from the expression of genes encoded in physically separated genomes, namely the mitochondrial and nuclear DNA, to the coordinated assembly of components and cofactors building each individual complex and eventually the supercomplexes. The genetic cause underlying around half of the diagnosed mitochondrial disease cases is currently known. Many of these cases result from pathogenic variants in genes encoding structural subunits or additional factors directly involved in the assembly of the ETC complexes. Here, we review the historical and most recent findings concerning the clinical phenotypes and the molecular pathological mechanisms underlying this particular group of disorders.

Keywords: ATP production; biogenesis of the respiratory chain; mitochondrial disease; mitochondrial electrochemical gradient; mitochondrial potential; mitochondrial proton pumping; mitochondrial respiratory chain; oxidative phosphorylation; respiratory complex; respiratory supercomplex.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenosine Triphosphate* / genetics
  • Adenosine Triphosphate* / metabolism
  • Animals
  • DNA, Mitochondrial* / genetics
  • DNA, Mitochondrial* / metabolism
  • Electron Transport / genetics
  • Electron Transport Chain Complex Proteins* / genetics
  • Electron Transport Chain Complex Proteins* / metabolism
  • Humans
  • Mitochondria* / genetics
  • Mitochondria* / metabolism
  • Mitochondria* / pathology
  • Mitochondrial Diseases* / genetics
  • Mitochondrial Diseases* / metabolism
  • Mitochondrial Diseases* / pathology


  • DNA, Mitochondrial
  • Electron Transport Chain Complex Proteins
  • Adenosine Triphosphate