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Updated: May 28, 2025

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Mitofusin 2 displays fusion-independent roles in proteostasis surveillance

Mariana Joaquim1,2,3, Selver Altin1,2, Maria-Bianca Bulimaga1,2,3,4

  • 1Institute for Genetics, University of Cologne, Cologne, Germany.

Nature Communications
|February 10, 2025
PubMed

Insights

Mitofusin 2 (MFN2) acts as a crucial gatekeeper for cellular proteostasis, preventing protein aggregation independently of its role in mitochondrial shape. This discovery offers new therapeutic avenues targeting MFN2.

Area of Science:

  • Cell Biology
  • Mitochondrial Biology
  • Proteostasis

Background:

  • Mitochondria are vital organelles regulating cellular protein homeostasis (proteostasis).
  • The molecular mechanisms governing mitochondrial quality control, particularly under basal conditions, remain incompletely understood.
  • Mitofusins (MFNs) are key proteins involved in mitochondrial dynamics.

Purpose of the Study:

  • To investigate the role of Mitofusin 2 (MFN2) in cellular proteostasis beyond its known function in mitochondrial fusion.
  • To identify molecular interactions and pathways regulated by MFN2 in maintaining protein quality control.
  • To explore the implications of MFN2 dysfunction in disease contexts.

Main Methods:

  • Mitochondrial protein analysis in MFN2 knockout (KO) cells and patient fibroblasts.
  • Co-immunoprecipitation assays to identify MFN2 interacting partners.
  • Assessment of protein aggregation and cellular proteostasis markers.
  • Functional rescue experiments by restoring MFN2 levels.

Main Results:

  • MFN2 deficiency leads to altered cellular proteome, including reduced import machinery and PINK1 accumulation.
  • MFN2 interacts with the proteasome and cytosolic chaperones, preventing protein aggregation.
  • Patient fibroblasts with MFN2 mutations exhibit significant protein aggregation defects.
  • MFN2 re-expression rescues proteostasis and mitochondrial fusion defects.

Conclusions:

  • MFN2 plays a critical, fusion-independent role in maintaining cellular proteostasis by preventing protein aggregation.
  • MFN2 acts as a molecular gatekeeper for quality control, interacting with the proteasome and chaperones.
  • Dysfunction of MFN2 underlies protein aggregation pathologies observed in MFN2-related diseases.
  • Modulating MFN2 levels presents a potential therapeutic strategy for enhancing cellular homeostasis.

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