Identification of a novel protein MICS1 that is involved in maintenance of mitochondrial morphology and apoptotic release of cytochrome c

• Published in: Molecular biology of the cell 2008-06, Vol.19 (6), p.2597-2608
• Main Authors: Oka, Toshihiko, Sayano, Tomoko, Tamai, Shoko, Yokota, Sadaki, Kato, Hiroki, Fujii, Gen, Mihara, Katsuyoshi
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein - metabolism; Cytochromes c - metabolism; Down-Regulation; HeLa Cells; Humans; Immunoprecipitation; Intracellular Signaling Peptides and Proteins - metabolism; Membrane Proteins - metabolism; Mitochondria - metabolism; Mitochondria - ultrastructure; Mitochondrial Membranes - metabolism; Mitochondrial Proteins - metabolism; Permeability; Protein Transport; Serum; Up-Regulation
• ISSN: 1059-1524; 1939-4586; 1939-4586
• DOI: 10.1091/mbc.E07-12-1205

Mitochondrial morphology dynamically changes in a balance of membrane fusion and fission in response to the environment, cell cycle, and apoptotic stimuli. Here, we report that a novel mitochondrial protein, MICS1, is involved in mitochondrial morphology in specific cristae structures and the apoptotic release of cytochrome c from the mitochondria. MICS1 is an inner membrane protein with a cleavable presequence and multiple transmembrane segments and belongs to the Bi-1 super family. MICS1 down-regulation causes mitochondrial fragmentation and cristae disorganization and stimulates the release of proapoptotic proteins. Expression of the anti-apoptotic protein Bcl-XL does not prevent morphological changes of mitochondria caused by MICS1 down-regulation, indicating that MICS1 plays a role in maintaining mitochondrial morphology separately from the function in apoptotic pathways. MICS1 overproduction induces mitochondrial aggregation and partially inhibits cytochrome c release during apoptosis, regardless of the occurrence of Bax targeting. MICS1 is cross-linked to cytochrome c without disrupting membrane integrity. Thus, MICS1 facilitates the tight association of cytochrome c with the inner membrane. Furthermore, under low-serum condition, the delay in apoptotic release of cytochrome c correlates with MICS1 up-regulation without significant changes in mitochondrial morphology, suggesting that MICS1 individually functions in mitochondrial morphology and cytochrome c release.