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. 2022 Mar 24;13:1582. doi: 10.1038/s41467-022-29071-4

Fig. 9. Models for how clu/CLUH promotes mitochondrial fission through regulating Drp1, and how functions of clu-drp1 interact with those of PINK1-parkin-mfn.

Fig. 9

a In wild-type cells, Drosophila Clueless and mammalian CLUH promote mitochondrial fission through regulating the recruitment of Drp1 from the cytosol to the OMM. In mammalian cells, this is accomplished by CLUH directly binding both mRNA and protein for Drp1 receptors Mff and MiD49. Moreover, CLUH regulates Mff and MiD49 protein levels through translational control. In Drosophila and mammalian cells, PINK1 and Parkin inhibit mitochondrial fusion by promoting degradation of Mfn proteins (Drosophila Marf, mammalian homologs Mfn1 and Mfn2). Together, the two pathways, clu-drp1 and PINK1-parkin-mfn, balance the opposing actions of mitochondrial fission and fusion and maintain mitochondrial integrity and tissue health. b Loss of clueless/CLUH results in decreased levels of Drp1 receptor proteins due to dysregulated translation. This further leads to decreased recruitment of Drp1 onto the OMM, reduced mitochondrial fission, mitochondrial dysfunction, and tissue damage.