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Genes Cells. 2016 May;21(5):408-24. doi: 10.1111/gtc.12351. Epub 2016 Mar 3.

Distinct types of protease systems are involved in homeostasis regulation of mitochondrial morphology via balanced fusion and fission.

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Department of Protein Biochemistry, Institute of Life Science, Kurume University, Kurume, 839-0864, Japan.
Institute for Genetics, CECAD, University of Cologne, 50674, Cologne, Germany.
Biological Systems Control Team, Biomedicinal Information Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo, 135-0064, Japan.
Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Fukuoka, 812-8582, Japan.


Mitochondrial morphology is dynamically regulated by fusion and fission. Several GTPase proteins control fusion and fission, and posttranslational modifications of these proteins are important for the regulation. However, it has not been clarified how the fusion and fission is balanced. Here, we report the molecular mechanism to regulate mitochondrial morphology in mammalian cells. Ablation of the mitochondrial fission, by repression of Drp1 or Mff, or by over-expression of MiD49 or MiD51, results in a reduction in the fusion GTPase mitofusins (Mfn1 and Mfn2) in outer membrane and long form of OPA1 (L-OPA1) in inner membrane. RNAi- or CRISPR-induced ablation of Drp1 in HeLa cells enhanced the degradation of Mfns via the ubiquitin-proteasome system (UPS). We further found that UPS-related protein BAT3/BAG6, here we identified as Mfn2-interacting protein, was implicated in the turnover of Mfns in the absence of mitochondrial fission. Ablation of the mitochondrial fission also enhanced the proteolytic cleavage of L-OPA1 to soluble S-OPA1, and the OPA1 processing was reversed by inhibition of the inner membrane protease OMA1 independent on the mitochondrial membrane potential. Our findings showed that the distinct degradation systems of the mitochondrial fusion proteins in different locations are enhanced in response to the mitochondrial morphology.

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