The Role of Mitochondrial DNA Mutations in Mammalian Aging

Mitochondrial DNA (mtDNA) accumulates both base-substitution mutations and deletions with aging in several tissues in mammals. Here, we examine the evidence supporting a causative role for mtDNA mutations in mammalian aging. We describe and compare human diseases and mouse models associated with mitochondrial genome instability. We also discuss potential mechanisms for the generation of these mutations and the means by which they may mediate their pathological consequences. Strategies for slowing the accumulation and attenuating the effects of mtDNA mutations are discussed

Transcription errors induce proteotoxic stress and shorten cellular lifespan

Transcription errors occur in all living cells; however, it is unknown how these errors affect cellular health. To answer this question, we monitored yeast cells that were genetically engineered to display error-prone transcription. We discovered that these cells suffer from a profound loss in proteostasis, which sensitizes them to the expression of genes that are associated with protein-folding diseases in humans; thus, transcription errors represent a new molecular mechanism by which cells can acquire disease. We further found that the error rate of transcription increases as cells age, suggesting that transcription errors affect proteostasis particularly in aging cells. Accordingly, transcription errors accelerate the aggregation of a peptide that is implicated in Alzheimer’s disease, and shorten the lifespan of cells. These experiments reveal a novel, basic biological process that directly affects cellular health and aging

Multiple Means to the Same End: The Genetic Basis of Acquired Stress Resistance in Yeast

In nature, stressful environments often occur in combination or close succession, and thus the ability to prepare for impending stress likely provides a significant fitness advantage. Organisms exposed to a mild dose of stress can become tolerant to what would otherwise be a lethal dose of subsequent stress; however, the mechanism of this acquired stress tolerance is poorly understood. To explore this, we exposed the yeast gene-deletion libraries, which interrogate all essential and non-essential genes, to successive stress treatments and identified genes necessary for acquiring subsequent stress resistance. Cells were exposed to one of three different mild stress pretreatments (salt, DTT, or heat shock) and then challenged with a severe dose of hydrogen peroxide (H2O2). Surprisingly, there was little overlap in the genes required for acquisition of H2O2 tolerance after different mild-stress pretreatments, revealing distinct mechanisms of surviving H2O2 in each case. Integrative network analysis of these results with respect to protein–protein interactions, synthetic–genetic interactions, and functional annotations identified many processes not previously linked to H2O2 tolerance. We tested and present several models that explain the lack of overlap in genes required for H2O2 tolerance after each of the three pretreatments. Together, this work shows that acquired tolerance to the same severe stress occurs by different mechanisms depending on prior cellular experiences, underscoring the context-dependent nature of stress tolerance

Human Disease-Associated Mutations in Genes Involved in mtDNA Replication and Maintenance

<div><p>Mutations reported in POLG [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030024#pgen-0030024-b036" target="_blank">36</a>,<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030024#pgen-0030024-b151" target="_blank">151</a>–<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030024#pgen-0030024-b162" target="_blank">162</a>], TWINKLE (gene also known as <i>PEO1</i>) [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030024#pgen-0030024-b034" target="_blank">34</a>,<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030024#pgen-0030024-b038" target="_blank">38</a>,<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030024#pgen-0030024-b039" target="_blank">39</a>,<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030024#pgen-0030024-b163" target="_blank">163</a>–<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030024#pgen-0030024-b167" target="_blank">167</a>], and ANT1 (gene also known as <i>SLC25A4</i>) [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030024#pgen-0030024-b035" target="_blank">35</a>,<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030024#pgen-0030024-b040" target="_blank">40</a>] proteins associated with human diseases.</p> <p>Mutations in black are associated with PEO, those in blue are associated with Alpers syndrome, red indicates mutations present in both PEO and Alpers, and green indicates mutations associated with other disorders. Italics indicate changes in DNA sequence.</p> <p>A) POLG. The light green and light blue segments represent the exonuclease and polymerase domains, respectively. Highly conserved motifs within each are shown as red segments. The POLG mutation figure is adapted from the Human DNA Polymerase Gamma Mutation Database maintained by the Mitochondrial Replication Group at the National Institute of Environmental Health Sciences (<a href="http://dir-apps.niehs.nih.gov/polg" target="_blank">http://dir-apps.niehs.nih.gov/polg</a>).</p> <p>B) TWINKLE. The pink domain is the primase-helicase linker region, as identified by homology to T7 phage protein [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030024#pgen-0030024-b034" target="_blank">34</a>].</p> <p>C) ANT1. In addition to the pathogenic mutations shown within the protein, a 3.3-kb deletion upstream of <i>ANT1</i> results in derepression of <i>ANT1</i> and is associated with facioscapulohumeral muscular dystrophy [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030024#pgen-0030024-b168" target="_blank">168</a>].</p> <p>Dup, duplication; fs, frameshift mutation; ins, insertion; *, termination codon</p></div

Multiple Molecular Mechanisms Rescue mtDNA Disease in C. elegans

Summary: Genetic instability of the mitochondrial genome (mtDNA) plays an important role in human aging and disease. Thus far, it has proven difficult to develop successful treatment strategies for diseases that are caused by mtDNA instability. To address this issue, we developed a model of mtDNA disease in the nematode C. elegans, an animal model that can rapidly be screened for genes and biological pathways that reduce mitochondrial pathology. These worms recapitulate all the major hallmarks of mtDNA disease in humans, including increased mtDNA instability, loss of respiration, reduced neuromuscular function, and a shortened lifespan. We found that these phenotypes could be rescued by intervening in numerous biological pathways, including IGF-1/insulin signaling, mitophagy, and the mitochondrial unfolded protein response, suggesting that it may be possible to ameliorate mtDNA disease through multiple molecular mechanisms. : Haroon et al. describe a genetically engineered C. elegans that carries an error-prone copy of DNA polymerase γ, the enzyme that replicates the mitochondrial genome. This worm recapitulates the major hallmarks of mitochondrial disease in humans. The authors identify multiple biological pathways that could potentially delay disease progression. Keywords: mitochondrial genome, mitophagy, mitochondrial unfolded protein response, IGF-1/insulin signaling, polymerase gamma, mutation, mitochondrial disease, mitochondrial DNA depletion, RNAi, neuromuscular dysfunctio