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

Abstract

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. INTRODUCTIONIn eukaryotic cells, mitochondria continuously divide and fuse, resulting in the formation of tubular network structures (Yaffe, 1999;Griparic and van der Bliek, 2001;Mozdy and Shaw, 2003). Various and diverse cellular events give rise to dynamically changing mitochondrial networks (Youle and Karbowski, 2005;Chan, 2006;McBride et al., 2006). Recent studies in yeast and mammalian cells revealed that the behaviors of these dynamic networks are controlled by distinct proteins, including OPA1/Mgm1, Drp1/Dnm1, Fis1, and Mfn1&2/Fzo1 (Yaffe, 1999;Jensen et al., 2000;Karbowski and Youle, 2003;Westermann, 2003;Zhang and Chan, 2007). In addition, a variety of factors, including DAP3, MTP18, MIB, and endophilin B1, directly or indirectly regulate mitochondrial morphology in mammals Mukamel and Kimchi, 2004;Tondera et al., 2005;Eura et al., 2006). The mitochondrion is an organelle with two different membranes: the outer and inner membranes. The outer membrane forms an envelope, and the inner membrane forms the cristae structure, comprising a narrow membrane that invaginates into the matrix. The cristae membrane is thought to be morphologically and functionally different from the inner boundary membrane along the outer membrane. For example, respiratory chains and ATP synthase preferentially distribute in the cristae membrane (Vogel et al., 2006). In certain yeast ATP synthase mutants, intramitochondrial onion-like structures are observed (Paumard et al., 2002). In mammals, mitofilin and OPA1 are involved in cristae morphology (Olichon et al., 2...

CHCM1/CHCHD6, Novel Mitochondrial Protein Linked to Regulation of Mitofilin and Mitochondrial Cristae Morphology

“…In addition to aforementioned proteins, OPA1 and MICS1 are two additional inner mitochondrial membrane proteins that are also linked to maintaining the integrity of cristae morphology (6,(7)(8)(9)11). In the case of OPA1 depletion, the mitochondria display "wider" (7) cristae structure (7-9), whereas MICS1 deficiency leads to "mild fragmentation, lump-like structures, and short curved tubules" (11) in mitochondrial cristae.…”

Transmembrane BAX Inhibitor Motif Containing (TMBIM) Family Proteins Perturbs a trans-Golgi Network Enzyme, Gb3 Synthase, and Reduces Gb3 Biosynthesis

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Mitochondrial dynamics and cancer

“…In mammals, there are at least eight isoforms of OPA1, produced by alternative splicing and proteolytic processing by mitochondrial proteases, yet the role of these isoforms is unclear. Other proteins have been reported to play a role in mitochondrial fusion such as Mitofilin which is involved in cristae morphology [18], MitoPLD a mitochondrial phospholipase D [19] and recently mitochondrial morphology and cristae structure (MICS1) an inner membrane protein necessary for maintenance of mitochondrial morphology in specific cristae structures [20]. Finally, the ␤-subunit of the protein phosphatase 2A (PPA2) has also been involved in mitochondrial dynamics [21].…”