Caspase-activated mitochondrial depolarization

Caspase 激活的线粒体去极化

• 批准号: 6847133
• 负责人: Lawrence H. Boise
• 金额: $ 27.27万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6847133
• 关键词: adenine nucleotides; adenosinetriphosphatase; apoptosis; cellular polarity; cysteine endopeptidases; cytochrome c; dendritic cells; electron transport; enzyme activity; enzyme inhibitors; free radical oxygen; human tissue; lipids; membrane potentials; mitochondrial membrane; monocyte; oxygen consumption; peroxidation

DESCRIPTION (provided by applicant): While apoptosis can be initiated by a wide variety of signals, the associated morphologic changes are invariant. This is based on the ability of diverse apoptotic signals to activate a common death pathway that is initiated by the release of apoptogenic factors from the mitochondria. At least two of these factors are involved in the activation of caspases. While most death signals require the release of factors from the mitochondria to activate the downstream caspases, signaling from death receptors can, in many cases, bypass the mitochondria. We have determined that Bcl-2/XL block cytochrome c release despite being unable to block death receptor-induced apoptosis. In contrast, loss of mitochondrial membrane potential (delta Sigma m) occurred to the same degree as in cells that cytochrome c release was observed. Maintenance of delta Sigma m required the inhibition of downstream caspases. Taken together these data suggest that Bcl-2/XL functions to control the release of apoptogenic factors while caspases mediate loss of Delta Sigma m. This suggests that in addition to targeting the cytoskeleton and genome, caspases target the mitochondria for inactivation. Based on the preliminary data presented within, we hypothesize that initiator caspases target the mitochondria to uncouple electron transport. This results in the production of reactive oxygen species. To prevent excessive production of reactive oxygen species that could be damaging to neighboring cells or the phagocyte effector caspases depolarize the mitochondria. The aims of this proposal are designed to further characterize caspase-dependent mitochondrial depolarization as well as to isolate the factor(s) responsible for loss of delta Sigma m. These results also have implications in the determination of the "point of no return" in apoptosis. We will also examine the effects of inhibiting caspase-dependent depolarization on the ability of cells to recover from a death stimulus as well as the phenotype of cells that recover. This has implications on the role of apoptosis in tumorigenesis and drug resistant cancer.

描述（由申请人提供）：虽然细胞凋亡可由多种信号启动，但相关的形态学变化是不变的。这是基于不同的凋亡信号激活共同死亡途径的能力，该途径由线粒体释放促凋亡因子启动。这些因子中至少有两种参与半胱天冬酶的激活。虽然大多数死亡信号需要从线粒体释放因子来激活下游半胱天冬酶，但在许多情况下，来自死亡受体的信号可以绕过线粒体。我们已经确定，Bcl-2/XL阻止细胞色素c的释放，尽管不能阻止死亡受体诱导的细胞凋亡。相比之下，线粒体膜电位（Δ Σ m）的损失发生的程度与细胞色素c释放的细胞中观察到的相同。Δ Σ m的维持需要抑制下游半胱天冬酶。总之，这些数据表明，Bcl-2/XL的功能，以控制释放的促凋亡因子，而半胱天冬酶介导的损失Δ Σ m。这表明，除了靶向细胞骨架和基因组，半胱天冬酶靶向线粒体失活。基于初步的数据，我们假设启动子半胱天冬酶靶向线粒体解偶联电子传递。这导致活性氧物质的产生。为了防止可能损害邻近细胞或吞噬细胞效应器的活性氧物质的过度产生，半胱天冬酶使线粒体脱保护。该提案的目的是进一步表征半胱天冬酶依赖性线粒体去极化以及分离导致Δ Σ m丢失的因子。这些结果也有影响，在确定的“点不归”的细胞凋亡。我们还将研究抑制半胱天冬酶依赖性去极化对细胞从死亡刺激中恢复的能力以及恢复的细胞表型的影响。这对细胞凋亡在肿瘤发生和耐药癌症中的作用具有启示。