A genomic analysis of chronological longevity factors in budding yeast

Burtner, Christopher R.; Murakami, Christopher J.; Olsen, Brady; Kennedy, Brian K.; Kaeberlein, Matt

doi:10.4161/cc.10.9.15464

Cited by 87 publications

(95 citation statements)

References 51 publications

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“…Conversely, overexpression of PaDNM1 in P. anserina shortens the life span (30). In yeast, ⌬mgm1 and ⌬fzo1 mutants, which exhibit abnormal mitochondrial fusion, have a shortened life span (31,32). Taken together, these findings suggest that aging is associated with mitochondrial fragmentation.…”

mentioning

confidence: 49%

“…Our attempts to obtain an N. crassa fzo1 knockout strain were also unsuccessful, which strongly suggests that the fzo1 gene is essential for viability of N. crassa. Conversely, deletion of FZO1 in budding yeast is not lethal but does lead to mtDNA loss, a respiration deficiency, an inability to grow on media containing a nonfermentable carbon source, and a shortened life span (19,20,31). However, mitofusins are essential for viability in almost all other eukaryotes.…”

Section: Discussionmentioning

confidence: 99%

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A uvs-5 Strain Is Deficient for a Mitofusin Gene Homologue, fzo1 , Involved in Maintenance of Long Life Span in Neurospora crassa

et al. 2013

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Mitochondria are highly dynamic organelles that continuously fuse and divide. To maintain mitochondria, cells establish an equilibrium of fusion and fission events, which are mediated by dynamin-like GTPases. We previously showed that an mus-10 strain, a mutagen-sensitive strain of the filamentous fungus Neurospora crassa, is defective in an F-box protein that is essential for the maintenance of mitochondrial DNA (mtDNA), long life span, and mitochondrial morphology. Similarly, a uvs-5 mutant accumulates deletions within its mtDNA, has a shortened life span, and harbors fragmented mitochondria, the latter of which is indicative of an imbalance between mitochondrial fission and fusion. Since the uvs-5 mutation maps very close to the locus of fzo1, encoding a mitofusin homologue thought to mediate mitochondrial outer membrane fusion, we determined the sequence of the fzo1 gene in the uvs-5 mutant. A single amino acid substitution (Q368R) was found in the GTPase domain of the FZO1 protein. Expression of wild-type FZO1 in the uvs-5 strain rescued the mutant phenotypes, while expression of a mutant FZO1 protein did not. Moreover, when knock-in of the Q368R mutation was performed on a wild-type strain, the resulting mutant displayed phenotypes identical to those of the uvs-5 mutant. Therefore, we concluded that the previously unidentified uvs-5 gene is fzo1. Furthermore, we used immunoprecipitation analysis to show that the FZO1 protein interacts with MUS-10, which suggests that these two proteins may function together to maintain mitochondrial morphology.

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confidence: 49%

Section: Discussionmentioning

confidence: 99%

A uvs-5 Strain Is Deficient for a Mitofusin Gene Homologue, fzo1 , Involved in Maintenance of Long Life Span in Neurospora crassa

et al. 2013

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“…Although high acetate has previously been associated with increased chronological aging in yeast (8,9), these previous studies were conducted with fermenting yeast cells with abundant glucose. In contrast, our studies with respiring yeast (as in Fig.…”

Section: Discussionmentioning

confidence: 99%

Superoxide Triggers an Acid Burst in Saccharomyces cerevisiae to Condition the Environment of Glucose-starved Cells

Baron¹,

Laws

Chen

et al. 2013

Journal of Biological Chemistry

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Background: During prolonged periods without glucose yeast cells acidify the extracellular environment. Results: This acid burst is derived from a mitochondrial aldehyde dehydrogenase and a cascade involving superoxide damage to the TCA cycle. Conclusion:The acid burst can condition the medium to improve cell growth. Significance: Damage from mitochondrial superoxide can be advantageous to cells during carbon starvation stress.

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“…Although GRE3 was previously found to be downregulated in a sir2D strain, it is further validated here as having a causative role as lifespan-extending gene 34 . Overall, this result constitutes a 10-fold increase over the expected frequency, as only 3.5% of the yeast genes are expected to extend CLS by random (Bernoulli's test, P-value ¼ 0.02, Methods) 33 . Of note, the ranking obtained by MOMA or the gene expression alone to the above genes is again markedly inferior (Supplementary Table S6).…”

Section: Transformationmentioning

confidence: 99%

“…5a, a highly significant enrichment for all treatments was found (Hypergeometric test, P-valueo9.99e-5). Further, we find that MTA's common predictions set is enriched with human orthologs of known lifespan-extending genes in yeast and Caenorhabditis elegans, collated from the SGD database and from the literature 28,[31][32][33]41 (Supplementary Data 4, Permutation test, empirical P-valueo0.02). Finally, a recently published study has examined the correlation between gene expression measured in mice livers and lifespan extension across different diet regimens 42 .…”

Section: Transformationmentioning

confidence: 99%

Model-based identification of drug targets that revert disrupted metabolism and its application to ageing

et al. 2013

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The growing availability of 'omics' data and high-quality in silico genome-scale metabolic models (GSMMs) provide a golden opportunity for the systematic identification of new metabolic drug targets. Extant GSMM-based methods aim at identifying drug targets that would kill the target cell, focusing on antibiotics or cancer treatments. However, normal human metabolism is altered in many diseases and the therapeutic goal is fundamentally different-to retrieve the healthy state. Here we present a generic metabolic transformation algorithm (MTA) addressing this issue. First, the prediction accuracy of MTA is comprehensively validated using data sets of known perturbations. Second, two predicted yeast lifespan-extending genes, GRE3 and ADH2, are experimentally validated, together with their associated hormetic effect. Third, we show that MTA predicts new drug targets for human ageing that are enriched with orthologs of known lifespan-extending genes and with genes downregulated following caloric restriction mimetic treatments. MTA offers a promising new approach for the identification of drug targets in metabolically related disorders.

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A genomic analysis of chronological longevity factors in budding yeast

Cited by 87 publications

References 51 publications

A uvs-5 Strain Is Deficient for a Mitofusin Gene Homologue, fzo1 , Involved in Maintenance of Long Life Span in Neurospora crassa

A uvs-5 Strain Is Deficient for a Mitofusin Gene Homologue, fzo1 , Involved in Maintenance of Long Life Span in Neurospora crassa

Superoxide Triggers an Acid Burst in Saccharomyces cerevisiae to Condition the Environment of Glucose-starved Cells

Model-based identification of drug targets that revert disrupted metabolism and its application to ageing

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