期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 44, 期 11, 页码 1935-1944出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2008.02.016
关键词
cardiolipin; cardiolipin synthase; cytochrome c; reactive oxygen species; free radicals
资金
- FIC NIH HHS [R03 TW007320-02, R03 TW007320] Funding Source: Medline
- NHLBI NIH HHS [R01 HL070755, R01 HL070755-05] Funding Source: Medline
- NIAID NIH HHS [U19 AI068021-030002, U19 AI068021] Funding Source: Medline
Cardiolipin (CL), a unique mitochondrial phospholipid synthesized by CL synthase (CLS), plays important, yet not fully understood, roles in mitochondria-dependent apoptosis. We manipulated CL levels in HeLa cells by knocking down CLS using RNA interference and selected a clone of CL-deficient cells with similar to 45% of its normal content. ESI-MS analysis showed that the CL molecular species were the same in CL-deficient and CL-sufficient cells. CL deficiency did not change mitochondrial functions (membrane potential, reactive oxygen species generation, cellular ATP levels) but conferred resistance to apoptosis induced by actinomycin D (Act[D), rotenone, or gamma-irradiation. During ActD-induced apoptosis, decreased CL peroxidation along with suppressed cytochrome (cyt) c release was observed in CL-deficient cells, whereas Bax translocation to mitochondria remained similar to that in CL-sufficient HeLa cells. The amounts of loosely bound cyt c (releasable under high ionic strength conditions) were the same in CL-deficient and CL-sufficient cells. Given that CL peroxidation during apoptosis is catalyzed by CL/cyt c complexes and CL oxidation products are essential for cyt c release from mitochondria, our results suggest that CL deficiency prevents adequate assembly of productive CL/cyt c complexes and CL peroxidation, resulting in increased resistance to apoptosis. (C) 2008 Elsevier Inc. All rights reserved.
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