Fis1 deficiency selects for compensatory mutations responsible for cell death and growth control defects

Area of Science:

• Cell Biology
• Genetics
• Molecular Biology

Background:

• Mitochondrial dynamics proteins, like Dnm1/Drp1 and Fis1, are crucial for mitochondrial fission and fusion.
• While Dnm1/Drp1 is conserved in promoting cell death, Fis1's role varies, acting in cell death in mammals but prosurvival in yeast.
• Genetic mutations in these proteins are linked to human neurological disorders.

Purpose of the Study:

• To investigate the consequences of Fis1 gene deletion in yeast.
• To identify secondary mutations that arise in Fis1 knockouts.
• To understand the functional impact of these compensatory mutations on cell death and growth regulation.

Main Methods:

• Yeast genetics: FIS1 gene knockout.
• Genomic analysis: Tiling arrays and genomic sequencing to identify mutations.
• Phenotypic analysis: Assessing mitochondrial respiratory defects (petite formation) and cell growth during amino-acid deprivation.

Main Results:

• Deletion of FIS1 consistently led to secondary mutations in the WHI2 gene.
• The WHI2 mutation caused premature termination, rescuing the petite phenotype associated with FIS1 deficiency.
• However, the WHI2 mutation resulted in impaired growth suppression during amino-acid deprivation.
• Fis1's survival function, compensated by WHI2, appears independent of Dnm1/Drp1 and Mdv1, potentially involving Caf4.

Conclusions:

• Loss of Fis1 imposes selection pressure for compensatory WHI2 mutations in yeast.
• These WHI2 mutations confer defective growth control and cell death regulation, resembling human tumor cells.
• Fis1 plays a critical long-term survival role in yeast, mediated possibly through Caf4, which is compensated by WHI2 mutations.