Regulation of oxidative phosphorylation, the mitochondrial membrane potential, and their role in human disease.
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.
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA. mhuttema@med.wayne.edu
Maik
M
Hüttemann
Icksoo
I
Lee
Alena
A
Pecinova
Petr
P
Pecina
Karin
K
Przyklenk
Jeffrey W
JW
Doan
D000494:Allosteric Regulation; D045304:Cytochromes c / Q000737:chemistry / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D028361:Mitochondrial Diseases / Q000209:etiology* / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D009569:Nitric Oxide / Q000378:metabolism; D010085:Oxidative Phosphorylation; D018892:Proton-Motive Force; D015398:Signal Transduction
D005609:Free Radicals; D009569:Nitric Oxide; D045304:Cytochromes c; D003576:Electron Transport Complex IV