Mitochondrial translocation of cyclin C stimulates intrinsic apoptosis through Bax recruitment. (6th August 2019)

• Record Type: Journal Article
• Authors: Jezek, Jan; Chang, Kai‐Ti; Joshi, Amogh M; Strich, Randy
• Is Part Of: EMBO reports. Volume 20:Number 9(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-08-06
• Subjects: apoptosis -- Bcl‐2 homology -- Cdk8 -- cyclin C -- mitochondria; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201847425
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: Intrinsic apoptosis requires mitochondrial outer membrane disruption triggered by recruitment, activation, and oligomerization of the Bcl‐2 homology protein Bax. Following oxidative stress, we demonstrated that the transcriptional regulator cyclin C is released into the cytosol where it directs mitochondrial fragmentation and efficient apoptotic induction. This study reveals that cytoplasmic cyclin C is required for both normal Bax activation and its efficient mitochondrial localization. This activity appears direct as cyclin C co‐immunoprecipitates with active Bax in stressed cells and binds recombinant Bax in vitro . In addition, stable cyclin C–Bax association requires the fission complex. Pharmacologically stimulating cyclin C nuclear release is sufficient for Bax association and their mitochondrial localization in the absence of any stress signals. However, these cells do not undergo cell death as Bax fails to oligomerize. These data support a model that cyclin C association defines an initial step in Bax mitochondrial recruitment and provides a physical connection between the fission and apoptotic factors. This strategy allows the cell to discriminate stress‐induced fission able to recruit Bax from other types of mitochondrial divisions. Synopsis: Cyclin C promotes Bax activation, recruitment to mitochondria and mitochondrial fragmentation, thereby initiating apoptosis in response to stress. Cytoplasmic cyclin C promotes Bax activation and its mitochondrial localization in response to stress. Cyclin C directly binds Bax in vitro . Cyclin C‐Bax interaction requires an intact mitochondrial fission complex. Cyclin C mediates mitochondrial fragmentation induced by stress. Abstract : Cyclin C promotes Bax activation, recruitment to mitochondria and mitochondrial fragmentation, thereby initiating apoptosis in response to stress.