Ataxia telangiectasia mutated influences cytochrome c oxidase activity

Patel, Abhishek; McDonald, T.; Spears, Larry D.; Ching, James Kain; Fisher, Jonathan S.

doi:10.1016/j.bbrc.2011.01.075

Cited by 33 publications

(26 citation statements)

References 27 publications

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“…46 Levels of complex I and ATP were also significantly decreased in the ATM-deficient thymocytes 46 ; in turn, these findings were consistent with those of previous studies showing that the activities of complex I and complex IV (cytochrome c oxidase) in mitochondria of ATMdeficient mice were greatly diminished in skeletal muscle and liver extracts, respectively. 92,93 It is interesting that Valentin-Vega et al 46 showed that the abnormally high mitochondrial mass, elevated mitochondrial respiration rates, and mitochondrial complex I deficiency in Atm 2/2 thymocytes could all be reversed when these cells were made heterozygous for the Beclin-1 gene, which encodes the Beclin-1 protein regulator of autophagy. It should be recognized, however, that the mechanisms by which Beclin-1 regulates mitochondrial biogenesis, as well as complexes of the mitochondrial ETC/OXPHOS system and respiration rates, require further elucidation.…”

Section: Atm and Mitochondriamentioning

confidence: 99%

Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions

Ambrose

Gatti²

2013

Blood

177

123

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In 1988, the gene responsible for the autosomal recessive disease ataxia- telangiectasia (A-T) was localized to 11q22.3-23.1. It was eventually cloned in 1995. Many independent laboratories have since demonstrated that in replicating cells, ataxia telangiectasia mutated (ATM) is predominantly a nuclear protein that is involved in the early recognition and response to double-stranded DNA breaks. ATM is a high-molecular-weight PI3K-family kinase. ATM also plays many important cytoplasmic roles where it phosphorylates hundreds of protein substrates that activate and coordinate cell-signaling pathways involved in cell-cycle checkpoints, nuclear localization, gene transcription and expression, the response to oxidative stress, apoptosis, nonsense-mediated decay, and others. Appreciating these roles helps to provide new insights into the diverse clinical phenotypes exhibited by A-T patients—children and adults alike—which include neurodegeneration, high cancer risk, adverse reactions to radiation and chemotherapy, pulmonary failure, immunodeficiency, glucose transporter aberrations, insulin-resistant diabetogenic responses, and distinct chromosomal and chromatin changes. An exciting recent development is the ATM-dependent pathology encountered in mitochondria, leading to inefficient respiration and energy metabolism and the excessive generation of free radicals that themselves create life-threatening DNA lesions that must be repaired within minutes to minimize individual cell losses.

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Section: Atm and Mitochondriamentioning

confidence: 99%

Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions

Ambrose

Gatti²

2013

Blood

177

123

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“…Recently, ATM was found to regulate the levels of reactive oxygen species (ROS) in mammalian cells (6) but the source of this ROS remains unclear. Although mitochondrial leakage has been suggested as the primary ROS source, other work indicates that alternative uncharacterized sources may be important (7).…”

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confidence: 99%

NADPH oxidase 4 is a critical mediator in Ataxia telangiectasia disease

Weyemi

Redon

Aziz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Ataxia telangiectasia (A-T), a rare autosomal recessive disorder characterized by progressive cerebellar degeneration and a greatly increased incidence of cancer among other symptoms, is caused by a defective or missing ataxia telangiectasia mutated (ATM) gene. The ATM protein has roles in DNA repair and in the regulation of reactive oxygen species (ROS). Here, we provide, to our knowledge, the first evidence that NADPH oxidase 4 (NOX4) is involved in manifesting A-T disease. We showed that NOX4 expression levels are higher in A-T cells, and that ATM inhibition leads to increased NOX4 expression in normal cells. A-T cells exhibit elevated levels of oxidative DNA damage, DNA double-strand breaks and replicative senescence, all of which are partially abrogated by down-regulation of NOX4 with siRNA. Sections of degenerating cerebelli from A-T patients revealed elevated NOX4 levels. ATM-null mice exhibit A-T disease but they die from cancer before the neurological symptoms are manifested. Injecting Atm-null mice with fulvene-5, a specific inhibitor of NOX4 and NADPH oxidase 2 (NOX2), decreased their elevated cancer incidence to that of the controls. We conclude that, in A-T disease in humans and mice, NOX4 may be critical mediator and targeting it will open up new avenues for therapeutic intervention in neurodegeneration.

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“…Moreover A-T cells have lower cytochrome c oxidase activity than normal cells, which could explain their reduced respiratory activity; interestingly, treatment of normal cells with an ATM inhibitor also results in reduced cytochrome c oxidase activity [50]. While there are numerous external sources of ROS, the great majority of ROS within eukaryotic cells derives from the mitochondrion as by-products during the generation of adenosine triphosphate (ATP), through the process of oxidative phosphorylation.…”

Section: Atm and Mitochondriamentioning

confidence: 99%