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Vol. 19, Issue 6, 2597-2608, June 2008

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Identification of a Novel Protein MICS1 that is Involved in Maintenance of Mitochondrial Morphology and Apoptotic Release of Cytochrome c

Toshihiko Oka^*, Tomoko Sayano^*, Shoko Tamai^*, Sadaki Yokota, Hiroki Kato^*, Gen Fujii, and Katsuyoshi Mihara^*

*Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan; Section of Functional Morphology, Faculty of Pharmaceutical Science, Nagasaki International University, 859-3298 Nagasaki, Japan; and Pathology Division, National Cancer Center Research Institute, 104-0045 Tokyo, Japan

Submitted December 5, 2007; Revised March 26, 2008; Accepted April 3, 2008
Monitoring Editor: Janet Shaw

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.

Address correspondence to: Toshihiko Oka (okat{at}cell.med.kyushu-u.ac.jp) or Katsuyoshi Mihara (mihara{at}cell.med.kyushu-u.ac.jp)

Abbreviations used: Bi-1, Bax inhibitor-1; DSP, dithiobis (succinimidyl propionate); GFP, green fluorescent protein; LFG, life guard; OPA1, optic atrophy 1; RNAi, RNA interference.