tBid interaction with cardiolipin primarily orchestrates mitochondrial dysfunctions and subsequently activates Bax and Bak
tBid interaction with cardiolipin primarily orchestrates mitochondrial dysfunctions and subsequently activates Bax and Bak
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DOI：
10.1038/sj.cdd.4401571
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发表时间：
2005-06-01
影响因子：
12.4
通讯作者：
Petit, PX
中科院分区：
文献类型：
--
作者：
Gonzalvez, F;Pariselli, F;Petit, PX
TNFR1/Fas结合导致胞质BID裂解为截短BID(TbID)，后者转位到线粒体。我们证明，重组的TBID在体外诱导线粒体生物能量稳态的即时不稳定。这些改变导致线粒体状态-4呼吸轻微解偶联，伴随着抑制二磷酸腺苷(ADP)刺激的呼吸和磷酸化速率。高表达Bcl2和Bclxl的线粒体对线粒体动态平衡的破坏作用受到抑制。线粒体膜上心磷脂的重组间接影响ADP/ATP转运体的活性，从而抑制状态3呼吸。心磷脂缺乏的酵母线粒体没有表现出任何呼吸抑制，证明了心磷脂对TBID结合和活性的绝对需求。相反，野生型酵母线粒体经历了类似的ADP刺激的呼吸抑制，伴随着ATP合成的减少。这些事件表明，线粒体脂类而不是蛋白质是TBID诱导的线粒体生物能量学失稳的关键决定因素。
TNFR1/Fas engagement results in the cleavage of cytosolic Bid to truncated Bid (tBid), which translocates to mitochondria. We demonstrate that recombinant tBid induces in vitro immediate destabilization of the mitochondrial bioenergetic homeostasis. These alterations result in mild uncoupling of mitochondrial state-4 respiration, associated with an inhibition the adenosine diphosphate (ADP)-stimulated respiration and phosphorylation rate. tBid disruption of mitochondrial homeostasis was inhibited in mitochondria overexpressing Bcl-2 and Bcl-XL. The inhibition of state-3 respiration is mediated by the reorganization of cardiolipin within the mitochondrial membranes, which indirectly affects the activity of the ADP/ATP translocator. Cardiolipin-deficient yeast mitochondria did not exhibit any respiratory inhibition by tBid, proving the absolute requirement for cardiolipin for tBid binding and activity. In contrast, the wild-type yeast mitochondria underwent a similar inhibition of ADP-stimulated respiration associated with reduced ATP synthesis. These events suggest that mitochondrial lipids rather than proteins are the key determinants of tBid-induced destabilization of mitochondrial bioenergetics.