Mitochondrial depolarization in yeast zygotes inhibits clonal expansion of selfish mtDNA

Area of Science:

• Cell Biology
• Genetics
• Biochemistry

Background:

• Mitochondrial DNA (mtDNA) exists in multiple copies within cells, and competition between different variants influences cellular fate.
• Understanding the dynamics of mtDNA competition is crucial for comprehending cellular health and disease.

Purpose of the Study:

• To investigate the impact of mitochondrial inhibitors on the competition between wild-type and mutant mtDNA in yeast heteroplasmic zygotes.
• To elucidate the role of mitochondrial fission and autophagy in regulating mtDNA competition.

Main Methods:

• Utilized yeast Saccharomyces cerevisiae as a model system.
• Applied mitochondrial inhibitors (uncouplers, valinomycin) to alter mitochondrial transmembrane potential.
• Assessed the effects of inhibiting mitochondrial fission and autophagy-related genes (ATG8, ATG32, ATG33).
• Quantified the turnover rate of mitochondrially targeted GFP.

Main Results:

• Decreasing mitochondrial transmembrane potential favored wild-type mtDNA over selfish mtDNA.
• This effect was diminished in cells with disrupted mitochondrial fission or repressed autophagy genes.
• Mitochondrial depolarization increased the turnover rate of mitochondrially targeted GFP in zygotes.
• Vacuoles in treated zygotes contained DNA, indicating autophagic degradation of mitochondria.

Conclusions:

• Mitochondrial depolarization inhibits the clonal expansion of selfish mtDNA.
• This process is dependent on mitochondrial fission and autophagy, highlighting the activation of mitochondria quality control mechanisms.
• The findings provide insights into the regulation of mtDNA heteroplasmy and cellular response to mitochondrial stress.