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Specific Ablation of the Apoptotic Functions of Cytochrome c Reveals a Differential Requirement for Cytochrome c and Apaf-1 in Apoptosis

2005; Cell Press; Volume: 121; Issue: 4 Linguagem: Inglês

10.1016/j.cell.2005.03.016

1097-4172

Zhenyue Hao, Gordon S. Duncan, Chia‐Che Chang, Andrew Elia, Min Fang, Andrew Wakeham, Hitoshi Okada, Thomas Calzascia, YingJu Jang, Annick You-Ten, Wen-Chen Yeh, Pamela S. Ohashi, Xiaodong Wang, Tak W. Mak,

ATP Synthase and ATPases Research

As components of the apoptosome, a caspase-activating complex, cytochrome c (Cyt c) and Apaf-1 are thought to play critical roles during apoptosis. Due to the obligate function of Cyt c in electron transport, its requirement for apoptosis in animals has been difficult to establish. We generated “knockin” mice expressing a mutant Cyt c (KA allele), which retains normal electron transfer function but fails to activate Apaf-1. Most KA/KA mice displayed embryonic or perinatal lethality caused by defects in the central nervous system, and surviving mice exhibited impaired lymphocyte homeostasis. Although fibroblasts from the KA/KA mice were resistant to apoptosis, their thymocytes were markedly more sensitive to death stimuli than Apaf-1−/− thymocytes. Upon treatment with γ irradiation, procaspases were efficiently activated in apoptotic KA/KA thymocytes, but Apaf-1 oligomerization was not observed. These studies indicate the existence of a Cyt c- and apoptosome-independent but Apaf-1-dependent mechanism(s) for caspase activation.