Phosphorylation of Mammalian Cytochrome c and Cytochrome c Oxidase in the Regulation of Cell Destiny: Respiration, Apoptosis, and Human Disease

  • Maik Hüttemann
  • Icksoo Lee
  • Lawrence I. Grossman
  • Jeffrey W. Doan
  • Thomas H. Sanderson
Part of the Advances in Experimental Medicine and Biology book series (volume 748)


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.


Epidermal Growth Factor Receptor Reactive Oxygen Species Generation Electron Transport Chain Mitochondrial Reactive Oxygen Species Noonan Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by grant GM089900 from the National Institutes of Health, a Department of Defence USAMRAA National Oncogenomic and Molecular Imaging Center contract through the Karmanos Cancer Institute, Detroit, the Center for Molecular Medicine and Genetics, and the Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit.


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Maik Hüttemann
    • 1
    • 2
  • Icksoo Lee
    • 3
  • Lawrence I. Grossman
    • 1
    • 2
  • Jeffrey W. Doan
    • 3
  • Thomas H. Sanderson
    • 4
    • 5
  1. 1.Center for Molecular Medicine and Genetics, and Cardiovascular Research InstituteWayne State University School of MedicineDetroitUSA
  2. 2.Karmanos Cancer InstituteDetroitUSA
  3. 3.Center for Molecular Medicine and GeneticsWayne State University School of MedicineDetroitUSA
  4. 4.Cardiovascular Research InstituteWayne State University School of MedicineDetroitUSA
  5. 5.Department of Emergency MedicineWayne State University School of MedicineDetroitUSA

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