The DNA Repair Protein OGG1 Protects Against Obesity by Altering Mitochondrial Energetics in White Adipose Tissue

Komakula, Sai Santosh Babu; Tůmová, Jana; Kumaraswamy, Deeptha; Burchat, Natalie; Vartanian, Vladimir; Ye, Hong; Dobrzyń, Agnieszka; Lloyd, R. Stephen; Sampath, Harini

doi:10.1038/s41598-018-33151-1

Cited by 59 publications

(76 citation statements)

References 68 publications

(60 reference statements)

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“…Fecal samples were collected after 6 weeks of feeding. As with previous cohorts [26,60], Ogg1 -/mice gained more weight ( Fig 1A) and more fat mass ( Fig 1B) upon HFD-administration, relative to WT controls.…”

Section: Increased Body Weight and Adiposity In Ogg1 -/Mice Fed A Hfdsupporting

confidence: 87%

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: Increased Body Weight and Adiposity In Ogg1 -/Mice Fed A Hfdsupporting

confidence: 87%

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

et al. 2020

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“…OGG1 has two isoforms: nuclear and mitochondrial (11). Multiple approaches have demonstrated that mitochondrial OGG1 is crucial for maintenance cell survival, mitochondrial function, and energetics (26,27). Recognition and repair of 8-OH-dG lesions is carried out by the mitochondrial isoform, and we previously showed that Ogg1 −/− BMDMs were more sensitive to menadione-induced mtDNA oxidative damage, and that inflammation caused by oxidized DNA damage and dyslipidemia-induced metabolic stress resulted in accelerated atherosclerosis in Ogg1 −/− Ldlr −/− mice (22).…”

Section: Discussionmentioning

confidence: 99%

Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model

et al. 2020

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Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease in which type I interferons (IFN) play a key role. The IFN response can be triggered when oxidized DNA engages the cytosolic DNA sensing platform cGAS-STING, but the repair mechanisms that modulate this process and govern disease progression are unclear. To gain insight into this biology, we interrogated the role of oxyguanine glycosylase 1 (OGG1), which repairs oxidized guanine 8-Oxo-2 ′-deoxyguanosine (8-OH-dG), in the pristane-induced mouse model of SLE. Ogg1 −/− mice showed increased influx of Ly6C hi monocytes into the peritoneal cavity and enhanced IFN-driven gene expression in response to short-term exposure to pristane. Loss of Ogg1 was associated with increased auto-antibodies (anti-dsDNA and anti-RNP), higher total IgG, and expression of interferon stimulated genes (ISG) to longer exposure to pristane, accompanied by aggravated skin pathology such as hair loss, thicker epidermis, and increased deposition of IgG in skin lesions. Supporting a role for type I IFNs in this model, skin lesions of Ogg1 −/− mice had significantly higher expression of type I IFN genes (Isg15, Irf9, and Ifnb). In keeping with loss of Ogg1 resulting in dysregulated IFN responses, enhanced basal and cGAMP-dependent Ifnb expression was observed in BMDMs from Ogg1 −/− mice. Use of the STING inhibitor, H151, reduced both basal and cGAMP-driven increases, indicating that OGG1 regulates Ifnb expression through the cGAS-STING pathway. Finally, in support for a role for OGG1 in the pathology of cutaneous disease, reduced OGG1 expression in monocytes associated with skin involvement in SLE patients and the expression of OGG1 was significantly lower in lesional skin compared with non-lesional skin in patients with Discoid Lupus. Taken together, these data support an important role for OGG1 in protecting against IFN production and SLE skin disease.

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“…BER removes small non-helix distorting lesions such as oxidized and deaminated bases, alkylation damage, and single-strand breaks [112,113,114]. The importance of this pathway for the maintenance of mtDNA integrity is evidenced by the numerous pathological phenotypes described in human cohorts and animal models with defects in BER [81,82,115,116,117,118,119].…”

Section: Induction Of Mitochondrial Dna Damagementioning

confidence: 99%

Mitochondrial DNA Integrity: Role in Health and Disease

Sharma

Sampath

2019

Cells

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As the primary cellular location for respiration and energy production, mitochondria serve in a critical capacity to the cell. Yet, by virtue of this very function of respiration, mitochondria are subject to constant oxidative stress that can damage one of the unique features of this organelle, its distinct genome. Damage to mitochondrial DNA (mtDNA) and loss of mitochondrial genome integrity is increasingly understood to play a role in the development of both severe early-onset maladies and chronic age-related diseases. In this article, we review the processes by which mtDNA integrity is maintained, with an emphasis on the repair of oxidative DNA lesions, and the cellular consequences of diminished mitochondrial genome stability.

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The DNA Repair Protein OGG1 Protects Against Obesity by Altering Mitochondrial Energetics in White Adipose Tissue

Cited by 59 publications

References 68 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 DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model

Mitochondrial DNA Integrity: Role in Health and Disease

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