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Pivaloyloxtmethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation
(Biorg Med Chem, 2008)Nitrogenous bisphosphonate inhibitors of farnesyl disphosphate synthase have been used clinically for treatment of bone disease. Because many of their effects may be mediated by depletion of geranylgeranyl diphosphate, ... -
Inhibition of DNA double-strand break repair by the Ku heterodimer in mrx mutants of Saccharomyces cerevisiae
(DNA Repair, 2009)Yeast rad50 and mre11 nuclease mutants are hypersensitive to physical and chemical agents that induce DNA double-strand breaks (DSBs). This sensitivity was suppressed by elevating intracellular levels of TLC1, the RNA ... -
Synthesis and Biological Evaluation of a Series of Aromatic Bisphospohonates
(Bioorg Med Chem, 2010)Geminal bisphosphonates display varied biological activity depending on the nature of the substituents on the central carbon atom. For example, the nitrogenous bisphosphonates zoledronate and risedronate inhibit the enzyme ... -
Bisphosphonates Induce Autophagy by Depleting Geranylgeranyl Diphosphate
(J Pharmacol Exp Ther., 2011)Multiple studies have implicated the depletion of isoprenoid biosynthetic pathway intermediates in the induction of autophagy. However, the exact mechanism by which isoprenoid biosynthesis inhibitors induce autophagy has ... -
A Novel Squalene Synthase inhibitor Combined with a Statin or Nitrogenous Biphosphonate in vitro
(J. Lipid Res., 2011)Statins and nitrogenous bisphosphonates (NBP) inhibit 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR) and farnesyl diphosphate synthase (FDPS), respectively, leading to depletion of farnesyl diphosphate (FPP) and ... -
pH Neutralization Protects Against Reduction in Replicative Lifespan Following Chronological Aging in Yeast
(Cell Cycle, 2012)Chronological and replicative aging have been studied in yeast as alternative paradigms for post-mitotic and mitotic aging, respectively. It has been known for more than a decade that cells of the S288C background aged ... -
Quantitative determination of isopentenyl diphosphate in cultured mammalian cells
(Analytical Biochemistry, 2012)Isopentenyl diphosphate (IPP), an intermediate of the isoprenoid biosynthetic pathway (IBP), has several important biological functions, yet a method to determine its basal level has not been described. Here, we describe ... -
Dietary restriction and mitochondrial function link replicative and chronological aging in Saccharomyces cerevisiae
(Experimental Gerontology, 2012)Chronological aging of budding yeast cells result in a reduction in a subsequent replicative life span through unknown mechanisms. Here, we show that dietary restrictions during chronological aging delays the reduction ... -
Yeast Replicative Aging; A Paradigm for Defining Conserved Longevity Interventions
(FEMS Yeast Research, 2014)The finite replicative life span of budding yeast mother cells was demonstrated as early as 1959, but the idea that budding yeast could be used to model aging of multicellular eukaryotes did not enter the scientific ... -
mTOR Inhibition by Rapamycin Alleviates Mitochondrial Disease in the Ndufs4-Mouse Model of Leigh Syndrome
(Science, 2013)Mitochondrial dysfunction contributes to numerous health problems, including neurological and muscular degeneration, cardiomyopathies, cancer, diabetes, and pathologies of aging. Severe mitochondrial defects can result ... -
End-of-lfe Cell Cycle Arrest Contributes to Stochasticity of Yeast Replicative Aging
(FEMS Yeast Research, 2013)There is growing evidence that stochastic events play an important role in determining individual longevity. Studies in model organisms have demonstrated that genetically identical populations maintained under apparently ... -
Molecular Mechanisms Underlying Genotype-dependent Responses to Dietary Restrictions
(Aging Cell, 2013)Dietary restriction (DR) increases lifespan and attenuates age-related phenotypes in many organisms; however, the effects of DR on longevity of individuals in genetically heterogeneous populations is not well characterized. ... -
Buffering the pH of the Culture Medium does not Extend Yeast Replicative Lifespan
(F1000 Research, 2013)During chronological aging of the budding yeast cells, the culture medium can become acidified and this acidification limits cell survival. As a consequence, buffering the culture medium to pH 6 significantly extends ... -
Nar1 Deficiency Results in Shortened Lifespan and Sensitivity to Paraquat that is Rescued by Increased Expression of Mitochondrial Superoxide Dismutase
(Mech Ageing Dev, 2014)Saccaromyces cerevisiae Nar lp is an essential Fe/S protein that exhibits striking similarity to bacterial iron-only hydogenases. Nar1p is required for the maturation of cytosolic and nuclear, but not of mitochondrial ... -
PMT1 Deficiency Enhances Basal UPR Activity and Extends Replicative Lifespan of Sacchraromyces cerevisiae
(Age (Dordr), 2015)Pmt1p is an important member of the protein O-mannosyltransferase (PMT) family of enzymes, which participates in the endoplasmic reticulum (ER) unfolded protein response (UPR), an important pathway for alleviating ER stress. ... -
Defining Molecular Basis for the Longevity Traits in Natural Yeast Isolates
(NPJ Aging Mechanisms of Disease, 2015)Background: The budding yeast has served as a useful model organism in aging studies, leading to the identification of genetic determinants of longevity, many of which are conserved in higher eukaryotes. However, factors ... -
A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging
(Cell Metab, 2015)Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic analysis of yeast RLS in a ... -
Tether Mutations that Restore Function and Suppress Pleiotropic Phenotypes of the C. elegans isp-1(qm150) Rieske Iron-sulfur Protein
(PNAS, 2015)Mitochondria play an important role in numerous diseases as well as normative aging. Severe reduction in mitochondrial function contributes to childhood disorders such as Leigh Syndrome, whereas mild disruption can extend ... -
Restoring Membrane Protein Trafficking Rescues the Effects of Aneuploidy on Cellular Aging
(2016)Aneuploidy and aging are correlated; however, a causal link between these two phenomena has remained elusive. Here, we show that yeast disomic for a single native yeast chromosome generally have a decreased replicative ... -
New Functional and Biophysical Insights into the Mitochondrial Rieske Iron-Sulfur Protein from Genetic Suppressor Analysis
(WORM, 2016)Several intragenic mutations suppress the C. elegans isp-1 (qm150) allele of the mitochondrial Rieske iron-sulfur protein (ISP), a catalytic subunit of Complex III of the respiratory chain. These mutations were located ...
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