Deletion of conserved protein phosphatases reverses defects associated with mitochondrial DNA damage in Saccharomyces cerevisiae.
Mitochondrial biogenesis is regulated by signaling pathways sensitive to extracellular conditions and to the internal environment of the cell. Therefore, treatments for disease caused by mutation of mtDNA may emerge from studies of how signal transduction pathways command mitochondrial function. We have examined the role of phosphatases under the control of the conserved α4/Tap42 protein in cells lacking a mitochondrial genome. We found that deletion of protein phosphatase 2A (PP2A) or of protein phosphatase 6 (PP6) protects cells from the reduced proliferation, mitochondrial protein import defects, lower mitochondrial electrochemical potential, and nuclear transcriptional response associated with mtDNA damage. Moreover, PP2A or PP6 deletion allows viability of a sensitized yeast strain after mtDNA loss. Interestingly, the Saccharomyces cerevisiae ortholog of the mammalian AMP-activated protein kinase was required for the full benefits of PP6 deletion and also for proliferation of otherwise wild-type cells lacking mtDNA. Our work highlights the important role that nutrient-responsive signaling pathways can play in determining the response to mitochondrial dysfunction.
Department of Molecular Biology and Genetics and School of Medicine, Koç University, Sarıyer, Istanbul, 34450 Turkey.
Görkem
G
Garipler
Nebibe
N
Mutlu
Nathan A
NA
Lack
Cory D
CD
Dunn
D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics*; D005434:Flow Cytometry; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D017384:Sequence Deletion; D059467:Transcriptome
D004272:DNA, Mitochondrial; D010749:Phosphoprotein Phosphatases
TOR; bioenergetics; mitochondria; nutrient signaling; petite-negative