The Role Of Cytochrome C In Apoptosis: Increased Sensitivity To Tnf-a Is Associated With Respiratory Defects But Not With Lack Of Cytochrome C Release

Vempati, U., etc.
Mol Cell Biol, 2007

Although the role of cytochrome c in apoptosis is well established, details of its
participation in signaling pathways in vivo are not completely understood. The
knockout for the somatic isoform of cytochrome c caused embryonic lethality in
mice, but derived embryonic fibroblasts were shown to be resistant to apoptosis
induced by agents known to trigger the intrinsic apoptotic pathway. In contrast,
these cells were reported to be hypersensitive to TNF-a induced apoptosis, which
signals through the extrinsic pathway. Surprisingly, we found that this cell line
(CRL 2613) respired at close to normal levels because of an aberrant activation of a
testis isoform of cytochrome c, which albeit expressed at low levels, was able to
replace the somatic isoform for respiration and apoptosis. To produce a bona fide
cytochrome c knockout, we developed a mouse knockout for both the testis and
somatic isoforms of cytochrome c. The mouse was made viable by the introduction
of a ubiquitously expressed cytochrome c transgene flanked by loxP sites. Lung
fibroblasts in which the transgene was deleted showed no cytochrome c expression,
no respiration and resistance to agents that activate the intrinsic, and to a lesser but
significant extent, also the extrinsic pathways. Comparison of these cells with lines
with a defective oxidative phosphorylation system, showed that cells with defective
respiration have increased sensitivity to TNF-a induced apoptosis, but this process
was still amplified by cytochrome c. These studies underscore the importance of
oxidative phosphorylation and apoptosome function to both the intrinsic and
extrinsic apoptotic pathways.

Read more »

Mol Cell Biol
University of Miami, Miller School of Medicine