Human Fis1 regulates mitochondrial dynamics through inhibition of the fusion machinery

Abstract

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.

To Fis or not to Fuse? This is the question!

“…Moreover, the authors show that the effects of Fis1 overexpression on mitochondrial morphology are suppressed by latrunculin B. Actin assembly between ER and mitochondria is known to play an important role during Drp1‐dependent fission. The results of Yu et al () now suggest that Fis1 also contributes to mitochondrial dynamics in an actin‐dependent, but Drp1‐independent manner. It remains to be seen whether these actions of Fis1 also occur at the MAM or elsewhere.…”

“…In this context, Yu et al () focused on answering the question: Why Fis1 overexpression can still induce fragmentation in the absence of Drp1? They first tested the domains within Fis1 required to induce Drp1‐independent fragmentation and found that the presence of both cytosolic and transmembrane domains of Fis1 is required for fragmentation.…”

“…From there, Yu et al () test whether Fis1 might be promoting fission by recruiting dynamin 2 (Dyn2), previously shown to regulate Drp1‐induced fission. The finding that Fis1 can still fragment mitochondria in Drp1 −/− cells knocked down for Dyn2 supports that Fis1 overexpression fragments mitochondria by other non‐fission‐related mechanisms.…”

“…The finding that Fis1 can still fragment mitochondria in Drp1 −/− cells knocked down for Dyn2 supports that Fis1 overexpression fragments mitochondria by other non‐fission‐related mechanisms. This led to Yu et al () to test whether Fis1 could be inhibiting mitochondrial fusion, which also leads to mitochondrial fragmentation. They find that endogenous Fis1 immunoprecipitates with Mfn1, Mfn2 and OPA1 and that Fis1 is reducing the GTPase activity of Mfn1, Mfn2 and OPA1 when measured using cell‐free approaches.…”

“…Mammalian Fis1 fragments mitochondria into small units and was initially considered a major mitochondrial fission factor, with this major role being challenged. Yu et al () define that Fis1 induces mitochondrial fragmentation by blocking mitochondrial fusion. This study highlights the limitation of categorizing mitochondrial dynamics proteins based on architecture measurements, given the general tendency to associate fragmentation with activation of fission.…”