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Defective mitochondrial gene expression results in reactive oxygen species-mediated inhibition of respiration and reduction of yeast life span.
Mol Cell Biol. 2006 Jul; 26(13):4818-29.MC

Abstract

Mitochondrial dysfunction causes numerous human diseases and is widely believed to be involved in aging. However, mechanisms through which compromised mitochondrial gene expression elicits the reported variety of cellular defects remain unclear. The amino-terminal domain (ATD) of yeast mitochondrial RNA polymerase is required to couple transcription to translation during expression of mitochondrial DNA-encoded oxidative phosphorylation subunits. Here we report that several ATD mutants exhibit reduced chronological life span. The most severe of these (harboring the rpo41-R129D mutation) displays imbalanced mitochondrial translation, conditional inactivation of respiration, elevated production of reactive oxygen species (ROS), and increased oxidative stress. Reduction of ROS, via overexpression of superoxide dismutase (SOD1 or SOD2 product), not only greatly extends the life span of this mutant but also increases its ability to respire. Another ATD mutant with similarly reduced respiration (rpo41-D152A/D154A) accumulates only intermediate levels of ROS and has a less severe life span defect that is not rescued by SOD. Altogether, our results provide compelling evidence for the "vicious cycle" of mitochondrial ROS production and lead us to propose that the amount of ROS generated depends on the precise nature of the mitochondrial gene expression defect and initiates a downward spiral of oxidative stress only if a critical threshold is crossed.

Authors+Show Affiliations

Department of Pathology, Yale University School of Medicine, 310 Cedar St., P.O. Box 208023, New Haven, CT 06520-8023, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16782871

Citation

Bonawitz, Nicholas D., et al. "Defective Mitochondrial Gene Expression Results in Reactive Oxygen Species-mediated Inhibition of Respiration and Reduction of Yeast Life Span." Molecular and Cellular Biology, vol. 26, no. 13, 2006, pp. 4818-29.
Bonawitz ND, Rodeheffer MS, Shadel GS. Defective mitochondrial gene expression results in reactive oxygen species-mediated inhibition of respiration and reduction of yeast life span. Mol Cell Biol. 2006;26(13):4818-29.
Bonawitz, N. D., Rodeheffer, M. S., & Shadel, G. S. (2006). Defective mitochondrial gene expression results in reactive oxygen species-mediated inhibition of respiration and reduction of yeast life span. Molecular and Cellular Biology, 26(13), 4818-29.
Bonawitz ND, Rodeheffer MS, Shadel GS. Defective Mitochondrial Gene Expression Results in Reactive Oxygen Species-mediated Inhibition of Respiration and Reduction of Yeast Life Span. Mol Cell Biol. 2006;26(13):4818-29. PubMed PMID: 16782871.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Defective mitochondrial gene expression results in reactive oxygen species-mediated inhibition of respiration and reduction of yeast life span. AU - Bonawitz,Nicholas D, AU - Rodeheffer,Matthew S, AU - Shadel,Gerald S, PY - 2006/6/20/pubmed PY - 2006/8/10/medline PY - 2006/6/20/entrez SP - 4818 EP - 29 JF - Molecular and cellular biology JO - Mol Cell Biol VL - 26 IS - 13 N2 - Mitochondrial dysfunction causes numerous human diseases and is widely believed to be involved in aging. However, mechanisms through which compromised mitochondrial gene expression elicits the reported variety of cellular defects remain unclear. The amino-terminal domain (ATD) of yeast mitochondrial RNA polymerase is required to couple transcription to translation during expression of mitochondrial DNA-encoded oxidative phosphorylation subunits. Here we report that several ATD mutants exhibit reduced chronological life span. The most severe of these (harboring the rpo41-R129D mutation) displays imbalanced mitochondrial translation, conditional inactivation of respiration, elevated production of reactive oxygen species (ROS), and increased oxidative stress. Reduction of ROS, via overexpression of superoxide dismutase (SOD1 or SOD2 product), not only greatly extends the life span of this mutant but also increases its ability to respire. Another ATD mutant with similarly reduced respiration (rpo41-D152A/D154A) accumulates only intermediate levels of ROS and has a less severe life span defect that is not rescued by SOD. Altogether, our results provide compelling evidence for the "vicious cycle" of mitochondrial ROS production and lead us to propose that the amount of ROS generated depends on the precise nature of the mitochondrial gene expression defect and initiates a downward spiral of oxidative stress only if a critical threshold is crossed. SN - 0270-7306 UR - https://www.unboundmedicine.com/medline/citation/16782871/Defective_mitochondrial_gene_expression_results_in_reactive_oxygen_species_mediated_inhibition_of_respiration_and_reduction_of_yeast_life_span_ L2 - http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=16782871 DB - PRIME DP - Unbound Medicine ER -