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Alternative oxidase causes cell type- and tissue-specific responses in mutator mice

Lilli Ikonen1, Sini Pirnes-Karhu2, Swagat Pradhan3

  • 1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland lilli.ikonen@helsinki.fi.

Life Science Alliance
|September 1, 2023
PubMed

Insights

Targeting reactive oxygen species (ROS) with alternative oxidase (AOX) shows cell-specific effects in mitochondrial disease models. While AOX delays anemia, it exacerbates muscle inflammation, indicating cautious therapeutic application.

Area of Science:

  • Mitochondrial biology and disease
  • Stem cell research
  • Oxidative stress and cellular signaling

Background:

  • Mitochondrial diseases involve energy deficits, excess reactive oxygen species (ROS), and aberrant signaling.
  • ROS regulate stem cell pools, but their impact on somatic stem cell homeostasis with targeted interventions is unclear.
  • Previous studies linked increased ROS to anemia in mitochondrial DNA mutator mice.

Purpose of the Study:

  • To investigate the effect of alternative oxidase (AOX) expression on murine stem cell pools and tissue homeostasis in mitochondrial DNA mutator mice.
  • To determine if attenuating ROS production via AOX impacts neural stem cells, erythroid progenitors, and skeletal muscle.
  • To assess the therapeutic potential of ROS-targeted interventions in a complex disease model.

Main Methods:

  • Utilized mitochondrial DNA mutator mice expressing the Ciona intestinalis alternative oxidase (AOX) ubiquitously.
  • Assessed the impact of AOX on neural stem cell populations.
  • Evaluated AOX effects on the progression of anemia and on inflammatory responses in skeletal muscle.

Main Results:

  • AOX expression did not affect neural stem cells but significantly delayed the progression of anemia in mutator mice.
  • In skeletal muscle, AOX potentiated mitochondrial stress and inflammatory responses when combined with the mutator.
  • Observed differential, cell type-specific effects of AOX, highlighting the complexity of mitochondrial interventions.

Conclusions:

  • AOX expression is not a universal solution for mitochondrial dysfunction.
  • ROS attenuation strategies require careful consideration of specific cellular defects and potential side effects.
  • Further research is needed to understand cell-specific responses before considering AOX for therapeutic use in mitochondrial diseases.

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