Mutations and deletions in the
mitochondrial genome (
mtDNA), as well as
instability of the nuclear genome, are involved in multiple human diseases. Here, we report that in
Saccharomyces cerevisiae, loss of
mtDNA leads to nuclear genome
instability, through a process of
cell-cycle arrest and
selection we define as a cellular crisis. This crisis is not mediated by the absence of respiration, but instead
correlates with a reduction in the
mitochondrial membrane potential. Analysis of cells undergoing this crisis identified a defect in
iron-sulfur cluster (ISC) biogenesis, which requires normal
mitochondrial function. We found that downregulation of nonmitochondrial ISC protein biogenesis was sufficient to cause increased genomic
instability in cells with intact
mitochondrial function. These results suggest
mitochondrial dysfunction stimulates nuclear genome
instability by inhibiting the production of ISC-containing protein(s), which are required for maintenance of nuclear genome integrity. For a video summary of this article, see the PaperFlick file available with the online Supplemental Data.
