Fluorescence Imaging of Mitochondrial DNA Base Excision Repair Reveals Dynamics of Oxidative Stress Responses

Jun, Yong Woong; Albarran, Eddy; Wilson, David L.; Ding, Jun; Kool, Eric T.

doi:10.1002/ange.202111829

Cited by 6 publications

(6 citation statements)

References 55 publications

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“…In the brain, no significant differences in OG accumulation have been found in Ogg1, Mutyh and DKO mice (3,34). To our knowledge, no other study has quantified OG in DNA glycosylase deficient HAP1 cells, however, one study analyzed repair capacity and found that OGG1 deficient HAP1 cells showed a higher rate of BER than WT cells at baseline (35) suggesting efficient compensation of other available DNA glycosylases in the absence of OGG1. A potential candidate is Nth-like DNA glycosylase 1 (NTHL1) that was shown to repair OG (36) and is also expressed at high levels in HAP1 cells (31).…”

Section: Discussionmentioning

confidence: 99%

Genomic 8-oxoguanine modulates gene transcription independent of its repair by DNA glycosylases OGG1 and MUTYH

Obermann,

Sakshaug,

Kanagaraj

et al. 2024

Preprint

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ABSTRACT8-oxo-7,8-dihydroguanine (OG) is one of the most abundant oxidative lesions in the genome and associated with genome instability. Its mutagenic potential is counteracted by a concerted action of 8-oxoguanine DNA glycosylase (OGG1) and mutY homolog DNA glycosylase (MUTYH). It has been suggested that OG and its repair has epigenetic-like properties and mediates transcription, but genome-wide evidence of this interdependence is lacking. Here, we applied an improved OG-sequencing approach reducing artificial background oxidation and RNA-sequencing to correlate genome-wide distribution of OG with gene transcription in OGG1 and/or MUTYH-deficient cells. Our data identified moderate enrichment of OG in the genome that is mainly dependent on the genomic context and not affected by DNA glycosylase-initiated repair. Interestingly, no association was found between genomic OG deposition and gene expression changes upon loss of OGG1 and MUTYH. Regardless of DNA glycosylase activity, OG in promoter regions correlated with expression of genes related to metabolic processes and damage response pathways indicating that OG functions as a cellular stress sensor to regulate transcription. Our work provides novel insights into the mechanism underlying transcriptional regulation by OG and DNA glycosylases OGG1 and MUTYH and suggests that oxidative DNA damage accumulation and its repair utilize different pathways.

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Section: Discussionmentioning

confidence: 99%

Genomic 8-oxoguanine modulates gene transcription independent of its repair by DNA glycosylases OGG1 and MUTYH

Obermann,

Sakshaug,

Kanagaraj

et al. 2024

Preprint

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“…Following exposure of the cells to an exogenous oxidating compound, mitochondrial BER was greatly elevated in the MTH1 KO cell line demonstrating the importance of sanitizing 8-oxoG precursors in mitochondria. The OGG1 KO cells showed lower BER activity than both MTH1 KO cells and the wild-type control cells resulting in the accumulation of 8-oxoG lesions in mtDNA (Jun et al, 2022).…”

Section: Disconnection Of Mtdna Damage and Mtdna Mutation Loadmentioning

confidence: 86%

“…Thus, despite recent reports showing that BER deficiency does not lead to increased mutation load in mtDNA or mtRNA in mice (Kauppila et al, 2018), the fact that BER, as well as the nucleotide pool sanitizing enzymes MTH1 and deoxyuridine nucleotidohydrolase (dUTPase) that eliminates dUTP, exist in mitochondria indicate the importance of preventing and repairing base lesions in mtDNA (Kang et al, 1995;Ladner and Caradonna, 1997;Ichikawa et al, 2008;Jun et al, 2022).…”

Section: Disconnection Of Mtdna Damage and Mtdna Mutation Loadmentioning

confidence: 98%

“…In a recent study, CRISPR-Cas9 based gene editing was used to generate cells lacking DNA glycosylase OGG1 that removes 8-oxoG from DNA, or MTH1 that hydrolyses 8-oxo-dGTP to 8oxo-dGMP to prevent its insertion into DNA. In vivo mitochondrial BER activity was measured in OGG1-and MTH1-deficient cells using a cell-and mitochondrialpermeable fluorescent probe that reacts with AP sites in mtDNA (Jun et al, 2022). Following exposure of the cells to an exogenous oxidating compound, mitochondrial BER was greatly elevated in the MTH1 KO cell line demonstrating the importance of sanitizing 8-oxoG precursors in mitochondria.…”

Section: Disconnection Of Mtdna Damage and Mtdna Mutation Loadmentioning

confidence: 99%

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Dynamic features of human mitochondrial DNA maintenance and transcription

Akbari

Nilsen

Montaldo

2022

Front. Cell Dev. Biol.

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Mitochondria are the primary sites for cellular energy production and are required for many essential cellular processes. Mitochondrial DNA (mtDNA) is a 16.6 kb circular DNA molecule that encodes only 13 gene products of the approximately 90 different proteins of the respiratory chain complexes and an estimated 1,200 mitochondrial proteins. MtDNA is, however, crucial for organismal development, normal function, and survival. MtDNA maintenance requires mitochondrially targeted nuclear DNA repair enzymes, a mtDNA replisome that is unique to mitochondria, and systems that control mitochondrial morphology and quality control. Here, we provide an overview of the current literature on mtDNA repair and transcription machineries and discuss how dynamic functional interactions between the components of these systems regulate mtDNA maintenance and transcription. A profound understanding of the molecular mechanisms that control mtDNA maintenance and transcription is important as loss of mtDNA integrity is implicated in normal process of aging, inflammation, and the etiology and pathogenesis of a number of diseases.

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“…Mitochondrial transcription factor A (TFAM), which is located in mitochondria, is necessary for mtDNA replication and mitochondrial biogenesis [9]. However, mtDNA lacks a mature self-repair system and is susceptible to mutations triggered by external disturbances [10]. mtDNA damage leads to cellular dysfunction and disease occurrence [11,12].…”

Section: Ivyspring International Publishermentioning

confidence: 99%

AKAP1 contributes to impaired mtDNA replication and mitochondrial dysfunction in podocytes of diabetic kidney disease

Feng¹,

Chen²,

Ma³

et al. 2022

Int. J. Biol. Sci.

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Podocyte injury is involved in the onset and progression of diabetic kidney disease (DKD) and is associated with mitochondrial abnormalities. Defective mitochondrial DNA (mtDNA) replication results in mitochondrial dysfunction. However, whether podocyte mtDNA replication is impaired in DKD is still unclear. A-kinase anchoring protein 1 (AKAP1) is localized in the outer mitochondrial membrane (OMM) and acts as a regulator and conductor of mitochondrial signals. Herein, we investigated the role of AKAP1 in high glucose-induced mtDNA replication. Decreased mtDNA replication and mitochondrial dysfunction occurred in podocytes of DKD. AKAP1 expression was up-regulated, and protein kinase C (PKC) signaling was activated under hyperglycemic conditions. AKAP1 recruited PKC and mediated La-related protein 1 (Larp1) phosphorylation, which reduced the expression of mitochondrial transcription factor A (TFAM), a key factor in mtDNA replication. In addition, mtDNA replication, mitochondrial function and podocyte injury were rescued by knocking down AKAP1 expression and the PKC inhibitor enzastaurin. In contrast, AKAP1 overexpression worsened the impairment of mtDNA replication and podocyte injury. In conclusion, our study revealed that AKAP1 phosphorylates Larp1 via PKC signaling activation to decrease mtDNA replication, which accelerates mitochondrial dysfunction and podocyte injury in DKD.

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Fluorescence Imaging of Mitochondrial DNA Base Excision Repair Reveals Dynamics of Oxidative Stress Responses

Cited by 6 publications

References 55 publications

Genomic 8-oxoguanine modulates gene transcription independent of its repair by DNA glycosylases OGG1 and MUTYH

Genomic 8-oxoguanine modulates gene transcription independent of its repair by DNA glycosylases OGG1 and MUTYH

Dynamic features of human mitochondrial DNA maintenance and transcription

AKAP1 contributes to impaired mtDNA replication and mitochondrial dysfunction in podocytes of diabetic kidney disease

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