Regulation of oxidative phosphorylation, the mitochondrial membrane potential, and their role in human disease

Maik Hüttemann, Icksoo Lee, Alena Pecinova, Petr Pecina, Karin Przyklenk, Jeffrey W. Doan

Research output: Contribution to journalReview articlepeer-review

185 Scopus citations


Thirty years after Peter Mitchell was awarded the Nobel Prize for the chemiosmotic hypothesis, which links the mitochondrial membrane potential generated by the proton pumps of the electron transport chain to ATP production by ATP synthase, the molecular players involved once again attract attention. This is so because medical research increasingly recognizes mitochondrial dysfunction as a major factor in the pathology of numerous human diseases, including diabetes, cancer, neurodegenerative diseases, and ischemia reperfusion injury. We propose a model linking mitochondrial oxidative phosphorylation (OxPhos) to human disease, through a lack of energy, excessive free radical production, or a combination of both. We discuss the regulation of OxPhos by cell signaling pathways as a main regulatory mechanism in higher organisms, which in turn determines the magnitude of the mitochondrial membrane potential: if too low, ATP production cannot meet demand, and if too high, free radicals are produced. This model is presented in light of the recently emerging understanding of mechanisms that regulate mammalian cytochrome c oxidase and its substrate cytochrome c as representative enzymes for the entire OxPhos system.

Original languageEnglish
Pages (from-to)445-456
Number of pages12
JournalJournal of Bioenergetics and Biomembranes
Issue number5
StatePublished - Oct 2008


  • Apoptosis
  • Cell signaling
  • Cytochrome c
  • Cytochrome c oxidase
  • Ischemia reperfusion injury
  • Membrane potential
  • Mitochondria
  • Neurodegenerative diseases
  • Oxidative phosphorylation
  • Reactive oxygen species


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