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Cited by 251

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Human Fis1 regulates mitochondrial dynamics through inhibition of the fusion machinery

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Yu, Rong, Jin, Shao‐Bo, Lendahl, Urban, Nistér, Monica, Zhao, Jian·2019·The EMBO Journal
DOI 10.15252/embj.201899748
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Abstract

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.

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Metadata

Authors
Yu, R., Jin, S., Lendahl, U., Nistér, M., & Zhao, J.
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2019-03-06
Volume
38
Issue
8
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
DOI
10.15252/embj.201899748
OpenAlex
W2921364326
Cited by
251
References
16
FWCI
10.31
Type
journal article
Language
en
Open access
hybrid
Licence
Funders
  • Swedish Cancer Society (CAN2014/836 (MN), CAN2017/737 (MN))
  • Cancer Society in Stockholm (2015‐151213 (MN), 2018‐181223 (MN))
  • Karolinska Institutet (2016fobi47658 (MN))
  • Swedish Research Council (K2014‐67X‐15399‐10‐4 (MN), ÄR‐MH2018‐02452 (MN), ÄR‐NT2015‐05542 (MN), ÄR‐NT2012‐5140 (MN))
  • Chinese Scholarship Council (2010622062 (RY))

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Yu, R., Jin, S., Lendahl, U., Nistér, M., & Zhao, J. (2019). Human Fis1 regulates mitochondrial dynamics through inhibition of the fusion machinery. The EMBO Journal. https://doi.org/10.15252/embj.201899748

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