title: Regulation of mitochondrial respiration and apoptosis through cell signaling: cytochrome c oxidase and cytochrome c in ischemia/reperfusion injury and inflammation.
abstract: Cytochrome c (Cytc) and cytochrome c oxidase (COX) catalyze the terminal reaction of the mitochondrial electron transport chain (ETC), the reduction of oxygen to water. This irreversible step is highly regulated, as indicated by the presence of tissue-specific and developmentally expressed isoforms, allosteric regulation, and reversible phosphorylations, which are found in both Cytc and COX. The crucial role of the ETC in health and disease is obvious since it, together with ATP synthase, provides the vast majority of cellular energy, which drives all cellular processes. However, under conditions of stress, the ETC generates reactive oxygen species (ROS), which cause cell damage and trigger death processes. We here discuss current knowledge of the regulation of Cytc and COX with a focus on cell signaling pathways, including cAMP/protein kinase A and tyrosine kinase signaling. Based on the crystal structures we highlight all identified phosphorylation sites on Cytc and COX, and we present a new phosphorylation site, Ser126 on COX subunit II. We conclude with a model that links cell signaling with the phosphorylation state of Cytc and COX. This in turn regulates their enzymatic activities, the mitochondrial membrane potential, and the production of ATP and ROS. Our model is discussed through two distinct human pathologies, acute inflammation as seen in sepsis, where phosphorylation leads to strong COX inhibition followed by energy depletion, and ischemia/reperfusion injury, where hyperactive ETC complexes generate pathologically high mitochondrial membrane potentials, leading to excessive ROS production. Although operating at opposite poles of the ETC activity spectrum, both conditions can lead to cell death through energy deprivation or ROS-triggered apoptosis.
authors.affiliation: Wayne State University School of Medicine, Detroit, MI 48201, USA. mhuttema@med.wayne.edu
authors.forename: Maik
authors.initials: M
authors.lastname: Hüttemann
authors.forename: Stefan
authors.initials: S
authors.lastname: Helling
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Sanderson
authors.forename: Christopher
authors.initials: C
authors.lastname: Sinkler
authors.forename: Lobelia
authors.initials: L
authors.lastname: Samavati
authors.forename: Gargi
authors.initials: G
authors.lastname: Mahapatra
authors.forename: Ashwathy
authors.initials: A
authors.lastname: Varughese
authors.forename: Guorong
authors.initials: G
authors.lastname: Lu
authors.forename: Jenney
authors.initials: J
authors.lastname: Liu
authors.forename: Rabia
authors.initials: R
authors.lastname: Ramzan
authors.forename: Sebastian
authors.initials: S
authors.lastname: Vogt
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Grossman
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Doan
authors.forename: Katrin
authors.initials: K
authors.lastname: Marcus
authors.forename: Icksoo
authors.initials: I
authors.lastname: Lee
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019069:Cell Respiration / Q000502:physiology; D045304:Cytochromes c / Q000378:metabolism*; D003576:Electron Transport Complex IV / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D003576:Electron Transport Complex IV