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Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs

Kiran Todkar1,2,3, Lilia Chikhi1,2, Véronique Desjardins1,2

  • 1Groupe de Recherche en Signalisation Cellulaire and Département de Biologie Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, Quebec, Canada.

Nature Communications
|March 31, 2021
PubMed

Insights

Cells prevent damaged mitochondrial proteins from entering extracellular vesicles (EVs) by sorting them into distinct Mitochondria-Derived Vesicles (MDVs). This mitochondrial quality control prevents inflammation by excluding damage-associated molecular patterns (DAMPs).

Area of Science:

  • Cell Biology
  • Mitochondrial Biology
  • Immunology

Background:

  • Cells release mitochondrial DNA and proteins via extracellular vesicles (EVs).
  • Mitochondria-Derived Vesicles (MDVs) mediate mitochondrial material transfer.
  • The role of mitochondrial content in non-inflammatory conditions is unclear.

Purpose of the Study:

  • To investigate how cells regulate the packaging of mitochondrial proteins into EVs.
  • To determine the mechanisms distinguishing functional from damaged mitochondrial cargo.
  • To elucidate the role of MDVs and specific proteins in this sorting process.

Main Methods:

  • Analysis of mitochondrial protein sorting into EVs and MDVs.
  • Investigating the roles of Optic Atrophy 1 (OPA1), sorting nexin 9 (Snx9), and Parkin in MDV pathways.
  • Utilizing cellular models to track mitochondrial content trafficking.

Main Results:

  • Cells actively exclude oxidized, pro-inflammatory mitochondrial proteins (DAMPs) from EVs.
  • Two distinct MDV pathways selectively target mitochondrial cargo.
  • OPA1/Snx9-dependent MDVs mediate EV packaging, while Parkin directs damaged cargo to lysosomes.

Conclusions:

  • Mitochondrial quality control mechanisms prevent the release of inflammatory mitochondrial DAMPs.
  • Selective MDV targeting dictates whether mitochondrial proteins enter EVs or are degraded.
  • This process highlights the interplay between mitochondrial quality control and immune response regulation.

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