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Human Fis1 regulates mitochondrial dynamics through inhibition of the fusion machinery
Rong Yu1, Shao-Bo Jin2, Urban Lendahl2
1Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
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 GTPases that drive mitochondrial fission and fusion. Fission is executed by the GTPases Drp1 and Dyn2, whereas the GTPases Mfn1, Mfn2, and OPA1 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 (hFis1) promotes fission through a similar mechanism as in yeast is not established. Here, we show that hFis1-mediated mitochondrial fragmentation occurs in the absence of Drp1 and Dyn2, suggesting that they are dispensable for hFis1 function. hFis1 instead binds to Mfn1, Mfn2, and OPA1 and inhibits their GTPase activity, thus blocking the fusion machinery. Consistent with this, disruption of the fusion machinery in Drp1-/- cells phenocopies the fragmentation phenotype induced by hFis1 overexpression. In sum, our data suggest a novel role for hFis1 as an inhibitor of the fusion machinery, revealing an important functional evolutionary divergence between yeast and mammalian Fis1 proteins.
Insights
Human Fis1 (hFis1) causes mitochondrial fragmentation independently of fission proteins. hFis1 inhibits mitochondrial fusion proteins, revealing evolutionary divergence from yeast Fis1.
Area of Science:
- Cell Biology
- Molecular Biology
- Mitochondrial Biology
Background:
- Mitochondrial dynamics, crucial for cellular function, rely on the balance between fission and fusion.
- Dynamin-related GTPases regulate mitochondrial fission (Drp1, Dyn2) and fusion (Mfn1, Mfn2, OPA1).
- The mechanism of human Fis1 (hFis1)-mediated mitochondrial fission is not fully understood, particularly its relation to yeast Fis1.
Purpose of the Study:
- To investigate the mechanism of hFis1-mediated mitochondrial fragmentation.
- To determine if Drp1 and Dyn2 are required for hFis1 function.
- To explore the evolutionary divergence in Fis1 function between yeast and mammals.
Main Methods:
- Investigated hFis1-mediated mitochondrial fragmentation in cells lacking Drp1 and Dyn2.
- Assessed the binding of hFis1 to Mfn1, Mfn2, and OPA1.
- Examined the GTPase activity of fusion proteins upon hFis1 binding.
- Compared hFis1 overexpression phenotype with fusion machinery disruption in Drp1-/- cells.
Main Results:
- hFis1 induced mitochondrial fragmentation even in the absence of Drp1 and Dyn2.
- hFis1 directly binds to Mfn1, Mfn2, and OPA1.
- hFis1 inhibits the GTPase activity of these fusion proteins, blocking mitochondrial fusion.
- Disruption of the fusion machinery phenocopied hFis1 overexpression effects.
Conclusions:
- hFis1 functions as an inhibitor of the mitochondrial fusion machinery, not by promoting fission.
- This mechanism highlights a significant functional evolutionary divergence between yeast and mammalian Fis1 proteins.
- hFis1's novel role provides new insights into the regulation of mitochondrial dynamics.
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