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

• Published in: Cell 2005-05, Vol.121 (4), p.579-591
• Main Authors: Hao, Zhenyue, Duncan, Gordon S., Chang, Chia-Che, Elia, Andrew, Fang, Min, Wakeham, Andrew, Okada, Hitoshi, Calzascia, Thomas, Jang, YingJu, You-Ten, Annick, Yeh, Wen-Chen, Ohashi, Pamela, Wang, Xiaodong, Mak, Tak W.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - physiology; Apoptosis - radiation effects; Apoptotic Protease-Activating Factor 1; Caspase 1; Caspases - metabolism; Caspases - radiation effects; Cytochromes c - genetics; Electron Transport - physiology; Electron Transport - radiation effects; Enzyme Activation - physiology; Enzyme Activation - radiation effects; Enzyme Precursors - metabolism; Enzyme Precursors - radiation effects; Gamma Rays; Lymphocyte Activation - genetics; Mice; Mice, Knockout; Mice, Mutant Strains; Mice, Transgenic; Nervous System Malformations - genetics; Nervous System Malformations - metabolism; Proteins - metabolism; T-Lymphocytes - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2005.03.016

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.