Mutation

Publication Title: 
Clinical and Experimental Pharmacology & Physiology

SUMMARY: The contractile function of the heart requires the release of Ca(2+) from intracellular Ca(2+) stores in the sarcoplasmic reticulum (SR) of cardiac muscle cells. The efficacy of Ca(2+) release depends on the amount of Ca(2+) loaded into the Ca(2+) store and the way in which this 'Ca(2+) load' influences the activity of the cardiac ryanodine receptor Ca(2+) release channel (RyR2).

Author(s): 
Dulhunty, Angela F.
Wium, Elize
Li, Linwei
Hanna, Amy D.
Mirza, Shamaruh
Talukder, Sadik
Ghazali, Nuur Aa
Beard, Nicole A.
Publication Title: 
Human Molecular Genetics

Niemann-Pick type C (NPC) disease, an autosomal recessive disorder caused primarily by loss-of-function mutations in NPC1 gene, is characterized neuropathologically by intracellular cholesterol accumulation, gliosis and neuronal loss in selected brain regions. Recent studies have shown that NPC disease exhibits intriguing parallels with Alzheimer's disease (AD), including the presence of tau-positive neurofibrillary tangles (NFTs) and ?-amyloid (A?)-related peptides in vulnerable brain regions. Since enhanced cholesterol level, which acts as a risk factor for AD, can increase A?

Author(s): 
Maulik, Mahua
Ghoshal, Bibaswan
Kim, John
Wang, Yanlin
Yang, Jing
Westaway, David
Kar, Satyabrata
Publication Title: 
Neurobiology of Aging

A number of neurological diseases are caused by mutations of RNA metabolism-related genes. A complicating issue is that whether under- or overfunction of such genes is responsible for the phenotype. Polyglutamine tract binding protein-1, a causative gene for X-linked mental retardation, is also involved in RNA metabolism, and both mutation and duplication of the gene were reported in human patients. In this study, we first report a novel phenotype of dPQBP1 (drosophila homolog of Polyglutamine tract binding protein-1)-mutant flies, lifespan shortening.

Author(s): 
Tamura, Takuya
Sone, Masaki
Nakamura, Yoko
Shimamura, Teppei
Imoto, Seiya
Miyano, Satoru
Okazawa, Hitoshi
Publication Title: 
PloS One

The human gene C10orf2 encodes the mitochondrial replicative DNA helicase Twinkle, mutations of which are responsible for a significant fraction of cases of autosomal dominant progressive external ophthalmoplegia (adPEO), a human mitochondrial disease caused by defects in intergenomic communication. We report the analysis of orthologous mutations in the Drosophila melanogaster mitochondrial DNA (mtDNA) helicase gene, d-mtDNA helicase.

Author(s): 
Sanchez-Martinez, Alvaro
Calleja, Manuel
Peralta, Susana
Matsushima, Yuichi
Hernandez-Sierra, Rosana
Whitworth, Alexander J.
Kaguni, Laurie S.
Garesse, Rafael
Publication Title: 
Molecular Cell

Cellular processes function through multistep pathways that are reliant on the controlled association and disassociation of sequential protein complexes. While dynamic action is critical to propagate and terminate work, the mechanisms used to disassemble biological structures are not fully understood. Here we show that the p23 molecular chaperone initiates disassembly of protein-DNA complexes and that the GCN5 acetyltransferase prolongs the dissociated state through lysine acetylation.

Author(s): 
Zelin, Elena
Zhang, Yang
Toogun, Oyetunji A.
Zhong, Sheng
Freeman, Brian C.
Publication Title: 
Antioxidants & Redox Signaling

SIGNIFICANCE: Among the most highly investigated theories of aging is the mitochondrial theory of aging. The basis of this theory includes a central role for altered or compromised mitochondrial function in the pathophysiologic declines associated with aging. In general, studies in various organisms, including nematodes, rodents, and humans, have largely upheld that aging is associated with mitochondrial dysfunction.

Author(s): 
Pulliam, Daniel A.
Bhattacharya, Arunabh
Van Remmen, Holly
Publication Title: 
PloS One

The immune response is essential for survival by destroying microorganisms and pre-cancerous cells. However, inflammation, one aspect of this response, can result in short- and long-term deleterious side-effects. Mclk1?/? mutant mice can be long-lived despite displaying a hair-trigger inflammatory response and chronically activated macrophages as a result of high mitochondrial ROS generation. Here we ask whether this phenotype is beneficial or simply tolerated. We used models of infection by Salmonella serovars and found that Mclk1?/?

Author(s): 
Wang, Dantong
Wang, Ying
Argyriou, Catherine
CarriËre, Audrey
Malo, Danielle
Hekimi, Siegfried
Publication Title: 
BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology

Mitochondrial function is achieved through the cooperative interaction of two genomes: one nuclear (nuDNA) and the other mitochondrial (mtDNA). The unusual transmission of mtDNA, predominantly maternal without recombination is predicted to affect the fitness of male offspring. Recent research suggests the strong sexual dimorphism in aging is one such fitness consequence. The uniparental inheritance of mtDNA results in a selection asymmetry; mutations that affect only males will not respond to natural selection, imposing a male-specific mitochondrial mutation load.

Author(s): 
Wolff, Jonci N.
Gemmell, Neil J.
Publication Title: 
Cell Death and Differentiation

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition with no cure. Mitochondrial dysfunction, Ca(2+) overloading and local hypoxic/ischemic environments have been implicated in the pathophysiology of ALS and are conditions that may initiate metabolic acidosis in the affected tissue. We tested the hypothesis that acidotoxicity and acid-sensing ion channels (ASICs) are involved in the pathophysiology of ALS. We found that motoneurons were selectively vulnerable to acidotoxicity in vitro, and that acidotoxicity was partially reduced in asic1a-deficient motoneuron cultures.

Author(s): 
Behan, A. T.
Breen, B.
Hogg, M.
Woods, I.
Coughlan, K.
Mitchem, M.
Prehn, J. H. M.
Publication Title: 
Biochimica Et Biophysica Acta

Hyperglycemia is a hallmark of diabetes that is associated with diabetic complications and a reduction of lifespan. Using the mev-1 mutant of the nematode Caenorhabditis elegans we here tried to identify molecular mechanisms underlying the lifespan reducing effects of glucose. The lowest glucose concentration tested (10mM) caused a significant lifespan reduction at 37∞C and was used to assess effects on mitochondrial efficiency, formation of protein carbonyls and levels of methylglyoxal, a precursor of advanced glycation end products (AGEs).

Author(s): 
Fitzenberger, Elena
Boll, Michael
Wenzel, Uwe

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