Editing Cytochrome c (section)

=== Role in apoptosis ===

Cytochrome c was also discovered in 1996 by [[Xiaodong Wang (biochemist)|Xiaodong Wang]] to have an intermediate role in [[apoptosis]], a controlled form of cell death used to kill cells in the process of development or in response to infection or DNA damage.<ref name="pmid8689682">{{Cite journal |vauthors=Liu X, Kim CN, Yang J, Jemmerson R, Wang X |date=July 1996 |title=Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c |journal=[[Cell (journal)|Cell]] |volume=86 |issue=1 |pages=147–57 |doi=10.1016/S0092-8674(00)80085-9 |pmid=8689682 |s2cid=12604356 |doi-access=free}}</ref>

Cytochrome c binds to [[cardiolipin]] in the inner mitochondrial membrane, thus anchoring its presence and keeping it from releasing out of the mitochondria and initiating apoptosis. While the initial attraction between cardiolipin and cytochrome c is electrostatic due to the extreme positive charge on cytochrome c, the final interaction is hydrophobic, where a hydrophobic tail from cardiolipin inserts itself into the hydrophobic portion of cytochrome c.{{cn|date=November 2024}}

During the early phase of apoptosis, mitochondrial ROS production is stimulated, and cardiolipin is oxidized by a peroxidase function of the cardiolipin–cytochrome c complex. The hemoprotein is then detached from the mitochondrial inner membrane and can be extruded into the soluble cytoplasm through pores in the outer membrane.<ref name="PMID16408030">{{Cite journal |vauthors=Orrenius S, Zhivotovsky B |date=September 2005 |title=Cardiolipin oxidation sets cytochrome c free |journal=Nature Chemical Biology |volume=1 |issue=4 |pages=188–9 |doi=10.1038/nchembio0905-188 |pmid=16408030 |s2cid=45381495}}</ref>

The sustained elevation in [[calcium]] levels precedes cyt ''c'' release from the mitochondria. The release of small amounts of cyt ''c'' leads to an interaction with the [[Inositol triphosphate receptor|IP3 receptor]] (IP3R) on the [[endoplasmic reticulum]] (ER), causing ER calcium release. The overall increase in calcium triggers a massive release of cyt ''c'', which then acts in the positive feedback loop to maintain ER calcium release through the IP3Rs.<ref name="pmid14608362">{{Cite journal |vauthors=Boehning D, Patterson RL, Sedaghat L, Glebova NO, Kurosaki T, Snyder SH |date=December 2003 |title=Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis |journal=Nature Cell Biology |volume=5 |issue=12 |pages=1051–61 |doi=10.1038/ncb1063 |pmid=14608362 |s2cid=27761335}}</ref> This explains how the ER calcium release can reach cytotoxic levels.  This  release of cytochrome c in turn activates [[caspase 9]], a cysteine [[protease]]. Caspase 9 can then go on to activate [[caspase 3]] and [[caspase 7]], which destroy the cell from within.{{cn|date=November 2024}}