Phosphorylation of mammalian cytochrome c and cytochrome c oxidase in the regulation of cell destiny: respiration, apoptosis, and human disease.
The mitochondrial oxidative phosphorylation (OxPhos) system not only generates the vast majority of cellular energy, but is also involved in the generation of reactive oxygen species (ROS), and apoptosis. Cytochrome c (Cytc) and cytochrome c oxidase (COX) represent the terminal step of the electron transport chain (ETC), the proposed rate-limiting reaction in mammals. Cytc and COX show unique regulatory features including allosteric regulation, isoform expression, and regulation through cell signaling pathways. This chapter focuses on the latter and discusses all mapped phosphorylation sites based on the crystal structures of COX and Cytc. Several signaling pathways have been identified that target COX including protein kinase A and C, receptor tyrosine kinase, and inflammatory signaling. In addition, four phosphorylation sites have been mapped on Cytc with potentially large implications due to its multiple functions including apoptosis, a pathway that is overactive in stressed cells but inactive in cancer. The role of COX and Cytc phosphorylation is reviewed in a human disease context, including cancer, inflammation, sepsis, asthma, and ischemia/reperfusion injury as seen in myocardial infarction and ischemic stroke.
Wayne State University School of Medicine, Detroit, MI, USA. mhuttema@med.wayne.edu
Maik
M
Hüttemann
Icksoo
I
Lee
Lawrence I
LI
Grossman
Jeffrey W
JW
Doan
Thomas H
TH
Sanderson
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D019069:Cell Respiration; D000242:Cyclic AMP / Q000502:physiology; D045304:Cytochromes c / Q000502:physiology*; D003576:Electron Transport Complex IV / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
D017382:Reactive Oxygen Species; D045304:Cytochromes c; D000242:Cyclic AMP; D003576:Electron Transport Complex IV; D011493:Protein Kinase C