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Two genomes, one destiny: Mitophagy at the crossroads of inheritance and disease

Chih-Yao Chung1, Kritarth Singh2, Brigida R Pinho3

  • 1Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, the Netherlands.

Cell Chemical Biology
|December 19, 2025
PubMed

Insights

Mitochondrial DNA mutations can evade cellular defenses during development by disabling the ubiquitin-proteasome system. Restoring this system via USP30 inhibition offers a promising therapeutic strategy for mitochondrial DNA disorders.

Area of Science:

  • Cellular Biology
  • Genetics
  • Developmental Biology

Background:

  • Mito-nuclear compatibility is crucial for cellular function but poorly understood.
  • Mitochondrial DNA (mtDNA) mutations can disrupt cellular homeostasis.
  • Embryogenesis requires precise regulation of genetic material.

Purpose of the Study:

  • To investigate how mitochondrial DNA mutations are managed during embryogenesis.
  • To identify mechanisms by which mtDNA mutations evade cellular surveillance.
  • To explore potential therapeutic targets for mtDNA disorders.

Main Methods:

  • Utilized a mouse model with a specific mtDNA mutation.
  • Investigated the role of the ubiquitin-proteasome system in mtDNA surveillance.
  • Examined the effect of USP30 inhibition on mitophagy and mutant mtDNA levels.

Main Results:

  • A specific mtDNA mutation was found to repress the ubiquitin-proteasome system during embryogenesis.
  • Inhibition of USP30 restored ubiquitin-mediated mitophagy.
  • USP30 inhibition led to a reduction in the burden of mutant mtDNA.

Conclusions:

  • The ubiquitin-proteasome system is a key component of mitochondrial surveillance against mtDNA mutations.
  • USP30 plays a critical role in regulating mitophagy and clearing mutant mtDNA.
  • Targeting USP30 presents a potential therapeutic avenue for treating mitochondrial DNA disorders.

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