Veatch, Joshua R. and McMurray, Michael A. and Nelson, Zara W. and Gottschling, Daniel E. (2009) Mitochondrial dysfunction leads to nuclear genome instability: A link through iron-sulfur clusters. Cell, 137 (7). pp. 1247-1258. ISSN 0092-8674
Preview |
Text (Complete manuscript)
GottschlingVeatchCell062909.pdf Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (956kB) | Preview |
Abstract
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 down-regulation of non-mitochondrial 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.
| Item Type: | Article or Abstract |
|---|---|
| Additional Information: | This article is available to subscribers only via the URL above for the first 12 months following publication. |
| DOI: | 10.1016/j.cell.2009.04.014 |
| PubMed ID: | 19563757 |
| NIHMSID: | NIHMS128788 |
| PMCID: | PMC2759275 |
| Grant Numbers: | T32 AG00057, AG023779, GM43893 |
| Keywords or MeSH Headings: | * Cell Aging * Cell Nucleus/genetics* * Genomic Instability* * Humans * Iron/metabolism * Iron-Sulfur Proteins/metabolism * Loss of Heterozygosity * Membrane Potential, Mitochondrial * Mitochondria/metabolism* * Saccharomyces cerevisiae/cytology* * Saccharomyces cerevisiae/metabolism* * Transcription, Genetic |
| Subjects: | Cellular and Organismal Processes > Genetic processes > Genomic instability |
| Depositing User: | Library Staff |
| Date Deposited: | 29 Jun 2009 21:59 |
| Last Modified: | 14 Feb 2012 14:42 |
| URI: | http://authors.fhcrc.org/id/eprint/304 |
Repository Administrators Only
 |
View Item |
