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Mitochondrial fission during mitophagy requires both inner and outer mitofissins

Kentaro Furukawa1, Tatsuro Maruyama2, Yuji Sakai3

  • 1Department of Cellular Physiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. furukawa.kentaro.828@m.kyushu-u.ac.jp.

EMBO Reports
|January 13, 2026
PubMed

Insights

Two mitofissins, Atg44 and mitofissin 2 (Mfi2), are essential for mitochondrial fission during mitophagy. Mfi2, located on the outer mitochondrial membrane, complements Atg44

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mitophagy maintains cellular health by removing damaged mitochondria.
  • Mitofissin/Atg44 was previously identified as a key factor in mitophagy-driven mitochondrial fission.
  • The sufficiency of mitofissin and the role of external factors in this process remained unclear.

Purpose of the Study:

  • To identify and characterize novel factors involved in mitophagy-associated mitochondrial fission.
  • To elucidate the mechanism and localization of these factors.
  • To understand the interplay between different fission machinery components.

Main Methods:

  • Yeast genetics and cell biology techniques.
  • In vitro lipid binding and membrane fission assays.
  • Coarse-grained molecular dynamics simulations.
  • Genetic interaction analyses.

Main Results:

  • A new protein, mitofissin 2 (Mfi2), residing on the outer mitochondrial membrane, was identified.
  • Mfi2 exhibits intrinsic mitofissin activity, binding to cardiolipin and mediating membrane fission.
  • Mfi2 and Dnm1 independently contribute to mitochondrial fission during mitophagy.
  • Overexpression of Mfi2's functional domain partially rescues mitophagy in cells lacking Atg44.

Conclusions:

  • Both Atg44 and Mfi2 are indispensable for mitophagy-associated mitochondrial fission.
  • Mfi2 acts as an intrinsic membrane fission factor, complementing Atg44's role.
  • Distinct but essential roles of Mfi2 and Dnm1 highlight a complex fission mechanism in mitophagy.
Keywords:
Atg44Mfi2Mitochondrial FissionMitofissinMitophagy

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