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

Mitochondrial morphology is dynamically regulated by fusion and fission. Several GTP ase 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 GTP ase mitofusins (Mfn1 and Mfn2) in outer membrane and long form of OPA 1 (L‐ OPA 1) in inner membrane. RNA i‐ 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 BAT 3/ BAG 6, 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‐ OPA 1 to soluble S‐ OPA 1, and the OPA 1 processing was reversed by inhibition of the inner membrane protease OMA 1 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.