Mitochondrial cytochrome c release: a factor to consider in mitochondrial disease?
The pathogenesis of mitochondrial disorders has largely focused on the impairment of cellular energy metabolism. However, mitochondrial dysfunction has also been implicated as a factor in the initiation of apoptosis due to the translocation of cytochrome c, from mitochondria to the cytosol, and the subsequent cleavage of pro-caspase 3. In this study, we determined the cytochrome c content of cytosols (skeletal muscle) prepared from 22 patients with evidence of compromised mitochondrial electron transport chain enzyme activity and 26 disease controls. The cytochrome c content of the mitochondrial electron transport chain-deficient group was found to be significantly (p < 0.02) elevated when compared with the control group (63.7 +/- 15.5 versus 27.7 +/- 2.5 ng/mg protein). Furthermore, a relationship between the cytosolic cytochrome c content of skeletal muscle and complex I and complex IV activities was demonstrated. Such data raise the possibility that mitochondrial cytochrome c release may be a feature of mitochondrial disorders, particularly for those patients with marked deficiencies of respiratory chain enzymes. Whether initiation of apoptosis occurs as a direct consequence of this cytochrome c release has not been fully evaluated here. However, for one patient with the greatest documented cytosolic cytochrome c content, caspase 3 could be demonstrated in the cytosolic preparation. Further work is required in order to establish whether a relationship also exists between caspase 3 formation and the magnitude of respiratory chain deficiency.
Oppenheim
M L S
ML
Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
Hargreaves
I P
IP
Pope
S
S
Land
J M
JM
Heales
S J R
SJ
D000293:Adolescent; D000328:Adult; D053148:Caspase 3 / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002950:Citrate (si)-Synthase / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology; D004579:Electron Transport / Q000502:physiology; D006801:Humans; D007202:Indicators and Reagents; D007223:Infant; D007231:Infant, Newborn; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology*; D028361:Mitochondrial Diseases / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology; D055815:Young Adult
D007202:Indicators and Reagents; D024101:Mitochondrial Proteins; D045304:Cytochromes c; D002950:Citrate (si)-Synthase; D053148:Caspase 3