RGD Reference Report - The role of oxidized cytochrome c in regulating mitochondrial reactive oxygen species production and its perturbation in ischaemia. - Rat Genome Database

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The role of oxidized cytochrome c in regulating mitochondrial reactive oxygen species production and its perturbation in ischaemia.

Authors: Pasdois, P  Parker, JE  Griffiths, EJ  Halestrap, AP 
Citation: Pasdois P, etal., Biochem J. 2011 Jun 1;436(2):493-505. doi: 10.1042/BJ20101957.
RGD ID: 7349317
Pubmed: PMID:21410437   (View Abstract at PubMed)
PMCID: PMC3195442   (View Article at PubMed Central)
DOI: DOI:10.1042/BJ20101957   (Journal Full-text)

Oxidized cytochrome c is a powerful superoxide scavenger within the mitochondrial IMS (intermembrane space), but the importance of this role in situ has not been well explored. In the present study, we investigated this with particular emphasis on whether loss of cytochrome c from mitochondria during heart ischaemia may mediate the increased production of ROS (reactive oxygen species) during subsequent reperfusion that induces mPTP (mitochondrial permeability transition pore) opening. Mitochondrial cytochrome c depletion was induced in vitro with digitonin or by 30 min ischaemia of the perfused rat heart. Control and cytochrome c-deficient mitochondria were incubated with mixed respiratory substrates and an ADP-regenerating system (State 3.5) to mimic physiological conditions. This contrasts with most published studies performed with a single substrate and without significant ATP turnover. Cytochrome c-deficient mitochondria produced more H(2)O(2) than control mitochondria, and exogenous cytochrome c addition reversed this increase. In the presence of increasing [KCN] rates of H(2)O(2) production by both pre-ischaemic and end-ischaemic mitochondria correlated with the oxidized cytochrome c content, but not with rates of respiration or NAD(P)H autofluorescence. Cytochrome c loss during ischaemia was not mediated by mPTP opening (cyclosporine-A insensitive), neither was it associated with changes in mitochondrial Bax, Bad, Bak or Bid. However, bound HK2 (hexokinase 2) and Bcl-xL were decreased in end-ischaemic mitochondria. We conclude that cytochrome c loss during ischaemia, caused by outer membrane permeabilization, is a major determinant of H(2)O(2) production by mitochondria under pathophysiological conditions. We further suggest that in hypoxia, production of H(2)O(2) to activate signalling pathways may be also mediated by decreased oxidized cytochrome c and less superoxide scavenging.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CycsRatnegative regulation of hydrogen peroxide biosynthetic process  IMP  RGD 
CycsRatpositive regulation of cellular respiration  IMP  RGD 
Bcl2l1Ratresponse to ischemia  IDA  RGD 
CycsRatresponse to ischemia  IDA  RGD 
Hk1Ratresponse to ischemia  IDA  RGD 
Hk2Ratresponse to ischemia  IDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Bcl2l1  (Bcl2-like 1)
Cycs  (cytochrome c, somatic)
Hk1  (hexokinase 1)
Hk2  (hexokinase 2)


Additional Information