Mitochondrial DNA Integrity: Role in Health and Disease

Sharma, Pulkit; Sampath, Harini

doi:10.3390/cells8020100

Cited by 169 publications

(137 citation statements)

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“…ROS exert their effects by altering the redox status of the cell and by reacting with and damaging cellular constituents. One of the important targets of ROS-induced damage is DNA, which is subject to oxidative lesions that must be repaired to maintain genomic stability [1][2][3]. Oxidatively induced DNA lesions are repaired primarily by the base excision repair (BER) pathway, in which excision of the damaged bases is initiated by DNA glycosylases.…”

Section: Introductionmentioning

confidence: 99%

“…Oxidatively induced DNA lesions are repaired primarily by the base excision repair (BER) pathway, in which excision of the damaged bases is initiated by DNA glycosylases. The enzyme 8-oxoguanine DNA glycosylase (OGG1) removes the most prevalent DNA lesions, 7,8-dihydro-8-oxoguanine (8-oxoG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua) from both genomic and mitochondrial DNA [1][2][3][4][5][6][7][8][9]. Deficiencies in OGG1 have been associated with several diseases including cancers [10][11][12][13][14], neurodegenerative diseases [15][16][17][18][19][20][21][22][23], and type 2 diabetes [24,25].…”

Section: Introductionmentioning

confidence: 99%

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OGG1 deficiency alters the intestinal microbiome and increases intestinal inflammation in a mouse model

et al. 2020

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OGG1-deficient (Ogg1 -/-) animals display increased propensity to age-induced and dietinduced metabolic diseases, including insulin resistance and fatty liver. Since the intestinal microbiome is increasingly understood to play a role in modulating host metabolic responses, we examined gut microbial composition in Ogg1 -/mice subjected to different nutritional challenges. Interestingly, Ogg1 -/mice had a markedly altered intestinal microbiome under both control-fed and hypercaloric diet conditions. Several microbial species that were increased in Ogg1 -/animals were associated with increased energy harvest, consistent with their propensity to high-fat diet induced weight gain. In addition, several pro-inflammatory microbes were increased in Ogg1 -/mice. Consistent with this observation, Ogg1 -/mice were significantly more sensitive to intestinal inflammation induced by acute exposure to dextran sulfate sodium. Taken together, these data indicate that in addition to their proclivity to obesity and metabolic disease, Ogg1 -/mice are prone to colonic inflammation. Further, these data point to alterations in the intestinal microbiome as potential mediators of the metabolic and intestinal inflammatory response in Ogg1 -/mice. OPEN ACCESS Citation: Simon H, Vartanian V, Wong MH, Nakabeppu Y, Sharma P, Lloyd RS, et al. (2020) OGG1 deficiency alters the intestinal microbiome and increases intestinal inflammation in a mouse model. PLoS ONE 15(1): e0227501. https://doi.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

OGG1 deficiency alters the intestinal microbiome and increases intestinal inflammation in a mouse model

et al. 2020

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“…Lipid peroxidation observed in schizophrenic patients causes changes in neuronal membranes, which consequently interferes with their function and affects signal transduction through changes in neurotransmitters and neuronal receptors located in postsynaptic membranes [96,97]. Oxidative damage also affects mitochondrial DNA [98], hence it can also contribute to impaired energy production, which is associated with free oxygen radicals, including superoxide anion radical O 2…”

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confidence: 99%

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

et al. 2020

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Schizophrenia is a neurodevelopmental disorder featuring chronic, complex neuropsychiatric features. The etiology and pathogenesis of schizophrenia are not fully understood. Oxidative-antioxidant imbalance is a potential determinant of schizophrenia. Oxidative, nitrosative, or sulfuric damage to enzymes of glycolysis and tricarboxylic acid cycle, as well as calcium transport and ATP biosynthesis might cause impaired bioenergetics function in the brain. This could explain the initial symptoms, such as the first psychotic episode and mild cognitive impairment. Another concept of the etiopathogenesis of schizophrenia is associated with impaired glucose metabolism and insulin resistance with the activation of the mTOR mitochondrial pathway, which may contribute to impaired neuronal development. Consequently, cognitive processes requiring ATP are compromised and dysfunctions in synaptic transmission lead to neuronal death, preceding changes in key brain areas. This review summarizes the role and mutual interactions of oxidative damage and impaired glucose metabolism as key factors affecting metabolic complications in schizophrenia. These observations may be a premise for novel potential therapeutic targets that will delay not only the onset of first symptoms but also the progression of schizophrenia and its complications.

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“…In contrast, ROS overproduction can induce oxidative damage to different mitochondrial components, including lipids such as cardiolipin, proteins involved in MRC activity or other metabolic processes and mtDNA (Musatov and Robinson, 2012;Sharma and Sampath, 2019).…”

Section: Production Of Reactive Oxygen Species and Their Deleteriousmentioning

confidence: 99%

Alteration of mitochondrial DNA homeostasis in drug-induced liver injury

Fromenty

2020

Food and Chemical Toxicology

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Mitochondrial DNA (mtDNA) encodes for 13 proteins involved in the oxidative phosphorylation (OXPHOS) process. In liver, genetic or acquired impairment of mtDNA homeostasis can reduce ATP output but also decrease fatty acid oxidation, thus leading to different hepatic lesions including massive necrosis and microvesicular steatosis. Hence, a severe impairment of mtDNA homeostasis can lead to liver failure and death. An increasing number of investigations report that some drugs can induce mitochondrial dysfunction and drug-induced liver injury (DILI) by altering mtDNA homeostasis. Some drugs such as ciprofloxacin, antiretroviral nucleoside reverse-transcriptase inhibitors and tacrine can inhibit hepatic mtDNA replication, thus inducing mtDNA depletion. Drug-induced reduced mtDNA levels can also be the consequence of reactive oxygen speciesmediated oxidative damage to mtDNA, which triggers its degradation by mitochondrial nucleases. Such mechanism is suspected for acetaminophen and troglitazone. Other pharmaceuticals such as linezolid and tetracyclines can impair mtDNA translation, thus selectively reducing the synthesis of the 13 mtDNA-encoded proteins. Lastly, some drugs might alter the mtDNA methylation status but the pathophysiological consequences of such alteration are still unclear. Drug-induced impairment of mtDNA homeostasis is probably under-recognized since preclinical and post-marketing safety studies do not classically investigate mtDNA levels, mitochondrial protein synthesis and mtDNA oxidative damage. 2 A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 2. Main features of the mitochondria 2.1. Structure and main components Mitochondria, whose size is ~1 µm, are intracellular organelles with two membranes (namely the outer and the inner membrane) that surround the matrix. This compartment contains numerous enzymes involved in different key oxidative pathways such as mitochondrial fatty acid oxidation (mtFAO) and pyruvate oxidation via the tricarboxylic acid (TCA) cycle. The matrix also contains the mitochondrial DNA (mtDNA) and all the components (e.g. enzymes and transcription factors) mandatory for its replication, transcription, translation and repair. However, this small genome allows only the synthesis of 13 polypeptides of the mitochondrial respiratory chain (MRC), whereas all other mitochondrial proteins (~1700) are encoded by the nuclear DNA and targeted to mitochondria (Area-Gomez and Schon, 2014; Borst and Grivell, 1981). Notably, mitochondria share different major features with bacteria including size, double-membrane structure, mode of mtDNA transcription and some components of the mtDNA translation machinery (Santini et al., 2017; Schon and Fromenty, 2015). These features are due to the fact that the precursors of mitochondria were bacteria that became endosymbiotic residents of "proto-eukaryotic" cells early in our evolutionary history (Pessayre et al., 2010). 2.2. Production of energy One major role of mitochondria is the production of energy so that these organelles...

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Mitochondrial DNA Integrity: Role in Health and Disease

Cited by 169 publications

References 212 publications

OGG1 deficiency alters the intestinal microbiome and increases intestinal inflammation in a mouse model

OGG1 deficiency alters the intestinal microbiome and increases intestinal inflammation in a mouse model

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

Alteration of mitochondrial DNA homeostasis in drug-induced liver injury

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