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Endosomal-dependent mitophagy coordinates mitochondrial nucleoid and mtDNA elimination

Ayesha Sen1, Julia Boix1,2, David Pla-Martín1,2

  • 1Center for Physiology and Pathophysiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Autophagy
|January 24, 2023
PubMed

Insights

Scientists discovered a new pathway for eliminating damaged mitochondrial DNA (mtDNA) using endosomal-mitophagy. This process, involving ATAD3 and SAMM50 proteins, removes mtDNA to prevent harmful immune responses and maintain cellular health.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Mitophagy is a crucial cellular process for removing damaged mitochondria.
  • Non-canonical mitophagy pathways, including endosomal-dependent mitophagy, are activated by specific cellular injuries.
  • Mitochondrial DNA (mtDNA) damage can trigger cellular dysfunction and inflammatory responses.

Purpose of the Study:

  • To elucidate a novel mechanism for mitochondrial nucleoid elimination upon mtDNA damage.
  • To identify key proteins involved in the endosomal-mitophagy pathway for mtDNA quality control.
  • To understand how this pathway prevents excessive immune activation.

Main Methods:

  • Proximity proteomics was employed to identify interacting proteins.
  • The study focused on the roles of ATAD3, SAMM50, and VPS35 in mtDNA extraction and sequestration.
  • Experiments investigated the endosomal-mitophagy pathway's function in response to mtDNA damage.

Main Results:

  • A new pathway was identified where mitochondrial nucleoids are eliminated via endosomal-mitophagy following mtDNA damage.
  • ATAD3 and SAMM50 were found to be essential for mtDNA extraction by controlling mitochondrial structure and nucleoid interaction.
  • SAMM50, in coordination with VPS35, facilitates the sequestration of mtDNA into endosomes for elimination, thereby mitigating immune responses.

Conclusions:

  • This study reveals a previously unknown endosomal-mitophagy pathway for clearing damaged mitochondrial nucleoids.
  • The identified proteins, ATAD3, SAMM50, and VPS35, play critical roles in mtDNA quality control and preventing inflammatory signaling.
  • This pathway represents a significant addition to our understanding of cellular defense mechanisms against mtDNA damage.
Keywords:
MitophagyendosomesmtDNA

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