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Mitochondrial dysfunction leads to nuclear genome instability: A link through iron-sulfur clusters

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

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Article URL: http://www.cell.com/fulltext/S0092-8674(09)00402-4

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
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

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