Levels of dna damage are unaltered in mice overexpressing human catalase in nuclei

Schriner, Samuel E.; Ogburn, Charles E.; Smith, Anthony; Newcomb, Terry; Ladiges, Warren; Dollé, Martijn E.T.; Vijg, Jan; Fukuchi, Ken Ichiro; Martin, George M.

doi:10.1016/s0891-5849(00)00352-x

Cited by 32 publications

(19 citation statements)

References 20 publications

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“…With the potential targets of free radical damage in mind, catalase was overexpressed in mice with a targeting signal for the peroxisome (endogenous sequence, PCAT), nucleus (NCAT), or mitochondrion (MCAT), under the control of a h actin promoter, which achieved high levels of expression, particularly in heart and muscle. Nuclear localization of NCAT (13) and mitochondrial localization of MCAT (14) was confirmed by immunofluorescence. In the MCAT animals, expression of mitochondrial catalase was robust but mosaic in nature (Fig.…”

Section: Introductionmentioning

confidence: 77%

Oxidative Damage and Aging: Spotlight on Mitochondria

2006

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Whereas free radical damage has been proposed as a key component in the tissue degeneration associated with aging, there has been little evidence that free radical damage limits life span in mammals. The current research shows that overexpression of the antioxidant enzyme catalase in mitochondria can extend mouse life span. These results highlight the importance of mitochondrial damage in aging and suggest that when targeted appropriately, boosting antioxidant defenses can increase mammalian life span. (Cancer Res 2006; 66(5): 2497-9)

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Section: Introductionmentioning

confidence: 77%

Oxidative Damage and Aging: Spotlight on Mitochondria

2006

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“…GPX1 −/− ,28, 252 SOD2 +/− ,240 extracellular SOD −/− 255, 256 and MSRB −/− 257 knockout murine models show no effect on lifespan. Similarly, transgenic animal models overexpressing RONS protective enzymes including SOD1 Tg ,26 SOD2 Tg ,24 MSRA Tg ,258 mice overexpressing human CAT in nuclei (nCAT Tg )259 and peroxisomal targeted CAT (pCAT Tg ) (the natural site of CAT)260 have failed to provide evidence of increased lifespan, indicating that RONS are not the fundamental determinants of lifespan. However, GPX4 +/− ,261 TRX1 Tg 262 and the mitochondrial CAT overexpressing (mCAT Tg ) mouse model263 showed ~7%, ~14% and ~21% increases in lifespan, respectively, which may provide support for the theory of oxidative damage in ageing.…”

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 99%

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

Sakellariou

Lightfoot

Earl

et al. 2017

J cachexia sarcopenia muscle

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Skeletal muscle is a major site of metabolic activity and is the most abundant tissue in the human body. Age‐related muscle atrophy (sarcopenia) and weakness, characterized by progressive loss of lean muscle mass and function, is a major contributor to morbidity and has a profound effect on the quality of life of older people. With a continuously growing older population (estimated 2 billion of people aged >60 by 2050), demand for medical and social care due to functional deficits, associated with neuromuscular ageing, will inevitably increase. Despite the importance of this ‘epidemic’ problem, the primary biochemical and molecular mechanisms underlying age‐related deficits in neuromuscular integrity and function have not been fully determined. Skeletal muscle generates reactive oxygen and nitrogen species (RONS) from a variety of subcellular sources, and age‐associated oxidative damage has been suggested to be a major factor contributing to the initiation and progression of muscle atrophy inherent with ageing. RONS can modulate a variety of intracellular signal transduction processes, and disruption of these events over time due to altered redox control has been proposed as an underlying mechanism of ageing. The role of oxidants in ageing has been extensively examined in different model organisms that have undergone genetic manipulations with inconsistent findings. Transgenic and knockout rodent studies have provided insight into the function of RONS regulatory systems in neuromuscular ageing. This review summarizes almost 30 years of research in the field of redox homeostasis and muscle ageing, providing a detailed discussion of the experimental approaches that have been undertaken in murine models to examine the role of redox regulation in age‐related muscle atrophy and weakness.

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“…The mtDNA genes have a much higher mutation rate than nDNA genes [Nachman et al, 1996;Schriner et al, 2000]. One factor contributing to the high mtDNA mutation rate is the proximity of mtDNA to mitochondrial ROS production.…”

Section: Mitochondrial Geneticsmentioning

confidence: 99%

Mitochondrial DNA mutations in disease and aging

Wallace

2010

Environ and Mol Mutagen

524

368

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The human mitochondrial genome involves over 1,000 genes, dispersed across the maternally inherited mitochondrial DNA (mtDNA) and the biparentally inherited nuclear DNA (nDNA). The mtDNA encodes 13 core proteins that determine the efficiency of the mitochondrial energy-generating system, oxidative phosphorylation (OXPHOS), plus the RNA genes for their translation within the mitochondrion. The mtDNA has a very high mutation rate, which results in three classes of clinically relevant mtDNA mutations: recently deleterious germline line mutations resulting in mitochondrial disease; ancient regional variants, a subset of which permitted humans to adapt to differences in their energetic environments; and somatic mutations that accumulate with age eroding mitochondrial energy production and providing the aging clock. Mutations in nDNA-encoded OXPHOS structural genes can also cause mitochondrial disease, and alterations in nDNA mitochondrial biogenesis genes can destabilize the mtDNA and lead to clinical phenotypes. Finally, when combined, nonpathogenic nDNA and mtDNA protein variants can be functionally incompatible and cause disease. The essential functions of the conserved mtDNA proteins and their high mutation rate raise the question as to why the cumulative mtDNA genetic load does not result in species extinction. Studies of mice harboring deleterious mtDNA mutations have shown that the mammalian ovary selectively eliminates the most deleterious mtDNA mutations. However, milder mtDNA mutations are transmitted through the ovary and the female germline and introduced into the general population. This unique genetic system provides a flexible method for generating genetic variation in cellular and organismal energetics that permits species to adapt to alterations in their regional energetic environment.

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Levels of dna damage are unaltered in mice overexpressing human catalase in nuclei

Cited by 32 publications

References 20 publications

Oxidative Damage and Aging: Spotlight on Mitochondria

Oxidative Damage and Aging: Spotlight on Mitochondria

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

Mitochondrial DNA mutations in disease and aging

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