Human Fis1 regulates mitochondrial dynamics through inhibition of the fusion machinery

Mitochondrial dynamics is important for life. At center stage for mitochondrial dynamics, the balance between mitochondrial fission and fusion is a set of dynamin‐related GTP ases that drive mitochondrial fission and fusion. Fission is executed by the GTP ases Drp1 and Dyn2, whereas the GTP ases Mfn1, Mfn2, and OPA 1 promote fusion. Recruitment of Drp1 to mitochondria is a critical step in fission. In yeast, Fis1p recruits the Drp1 homolog Dnm1p to mitochondria through Mdv1p and Caf4p, but whether human Fis1 ( hF is1) promotes fission through a similar mechanism as in yeast is not established. Here, we show that hF is1‐mediated mitochondrial fragmentation occurs in the absence of Drp1 and Dyn2, suggesting that they are dispensable for hF is1 function. hF is1 instead binds to Mfn1, Mfn2, and OPA 1 and inhibits their GTP ase activity, thus blocking the fusion machinery. Consistent with this, disruption of the fusion machinery in Drp1 −/− cells phenocopies the fragmentation phenotype induced by hF is1 overexpression. In sum, our data suggest a novel role for hF is1 as an inhibitor of the fusion machinery, revealing an important functional evolutionary divergence between yeast and mammalian Fis1 proteins.