Dual role of the OMM E3 Ub ligase MARCH5 in de novo peroxisome biogenesis and mitochondrial quality control through direct regulation of Pex26

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peroxisome biogenesis. Here we report that peroxisome biogenesis factor Pex26 is a MARCH5 client protein. In peroxisome-containing cells, MARCH5 interacts with Pex26 and facilitates the transfer of newly synthesized Pex26 from the OMM to peroxisomes. MARCH5 also controls peroxisomal delivery of other candidate peroxins in peroxisome-containing cells. On the other hand, in peroxisome-deficient cells, the turnover rate of Pex26 is dramatically increased, and MARCH5 targets this protein for p97-dependent proteasomal degradation. Both activities are mediated by MARCH5-dependent Pex26 ubiquitination. Knockout of Pex26 induces the accumulation of cells containing Tom20-positive, Catalase-deficient pre-peroxisomes. Further supporting the critical role of MARCH5 in peroxisome biogenesis, these structures are absent in Pex26/MARCH5 double knockout cells. The data support the model, where in peroxisome-containing cells, MARCH5 acts as a peroxisome biogenesis factor, while with defective peroxisome biogenesis, as in Zellweger syndrome cells, it protects mitochondria from potentially toxic accumulation of peroxins on the OMM.

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