Lower mitochondrial DNA content but not increased mutagenesis associates with decreased base excision repair activity in brains of AD subjects

Soltys, Daniela T.; Pereira, Carolina Parga Martins; Rowies, Fernanda T.; Farfel, José Marcelo; Grinberg, Lea T.; Suemoto, Cláudia Kimie; Leite, Renata; Rodriguez, Roberta Diehl; Ericson, Nolan G.; Bielas, Jason H.; Souza-Pinto, Nadja C.

doi:10.1016/j.neurobiolaging.2018.09.015

Cited by 27 publications

(36 citation statements)

References 66 publications

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“…AD brains had an average 63% increase in heteroplasmic mtDNA point mutations in the control-region (CR) and certain AD brains harbored the disease-specific CR mutations at levels up to 70-80% heteroplasmy, which preferentially altered regulatory elements of known mtDNA and suppressed transcription and replication of mtDNA [82]. However, conflicting results were reported since some groups found no changes in the aggregate burden of brain mtDNA point mutations between AD and control [83][84][85], which was probably owing to the small sample size and approach difference [86]. Lack of distinction of cell-specific mtDNA may also contribute to the variability since more sensitive studies by in situ hybridization [87] and laser capture microdissection in single hippocampus neurons or glial cells followed by a multiplex real-time qPCR method [88,89] demonstrated increased neuronal but not glial occurrence of mtDNA Δ4977 in AD.…”

Section: Disturbed Mitochondrial Genomic Homeostasis In Admentioning

confidence: 99%

“…In fact, levels of oxidized nucleic acids in mtDNA were found to be significantly elevated in preclinical Alzheimer's disease (PCAD) and MCI patients [94], suggesting that this is an early event during the course of disease. More recent studies demonstrated decreased OGG1 activity [95] and impaired base-excision repair (BER) activity in both AD and MCI patients [83], suggesting significant contribution of replication error to increased mtDNA mutations in AD [91]. Other modifications to mtDNA may also impact its transcription and function.…”

Section: Disturbed Mitochondrial Genomic Homeostasis In Admentioning

confidence: 99%

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Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances

Wang

Zhao

et al. 2020

Mol Neurodegeneration

780

506

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Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by impaired cognitive function due to progressive loss of neurons in the brain. Under the microscope, neuronal accumulation of abnormal tau proteins and amyloid plaques are two pathological hallmarks in affected brain regions. Although the detailed mechanism of the pathogenesis of AD is still elusive, a large body of evidence suggests that damaged mitochondria likely play fundamental roles in the pathogenesis of AD. It is believed that a healthy pool of mitochondria not only supports neuronal activity by providing enough energy supply and other related mitochondrial functions to neurons, but also guards neurons by minimizing mitochondrial related oxidative damage. In this regard, exploration of the multitude of mitochondrial mechanisms altered in the pathogenesis of AD constitutes novel promising therapeutic targets for the disease. In this review, we will summarize recent progress that underscores the essential role of mitochondria dysfunction in the pathogenesis of AD and discuss mechanisms underlying mitochondrial dysfunction with a focus on the loss of mitochondrial structural and functional integrity in AD including mitochondrial biogenesis and dynamics, axonal transport, ER-mitochondria interaction, mitophagy and mitochondrial proteostasis.

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Section: Disturbed Mitochondrial Genomic Homeostasis In Admentioning

confidence: 99%

Section: Disturbed Mitochondrial Genomic Homeostasis In Admentioning

confidence: 99%

Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances

Wang

Zhao

et al. 2020

Mol Neurodegeneration

780

506

View full text Add to dashboard Cite

show abstract

“…Studies investigating a role for DNA repair enzyme activity in AD brains have pointed to deficits in this process (Canugovi, Shamanna, Croteau, & Bohr, ; Lovell, Xie, & Markesbery, ; Weissman et al, ). From a mechanistic standpoint, there is evidence to link impaired base excision repair capacity in AD brains with lower mtDNA copy number (Soltys et al, ). Others speculate that oxidative stress (and not DNA repair capacity) is the main cause of aging‐dependent mtDNA damage (Wang et al, ).…”

Section: Evidence For Mitochondrial Dysfunction In Admentioning

confidence: 99%

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Ortiz

Swerdlow

2019

British J Pharmacology

333

178

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Dysfunction of cell bioenergetics is a common feature of neurodegenerative diseases, the most common of which is Alzheimer's disease (AD). Disrupted energy utilization implicates mitochondria at its nexus. This review summarizes some of the evidence that points to faulty mitochondrial function in AD and highlights past and current therapeutic development efforts. Classical neuropathological hallmarks of disease (β‐amyloid and τ) and sporadic AD risk genes (APOE) may trigger mitochondrial disturbance, yet mitochondrial dysfunction may incite pathology. Preclinical and clinical efforts have overwhelmingly centred on the amyloid pathway, but clinical trials have yet to reveal clear‐cut benefits. AD therapies aimed at mitochondrial dysfunction are few and concentrate on reversing oxidative stress and cell death pathways. Novel research efforts aimed at boosting mitochondrial and bioenergetic function offer an alternative treatment strategy. Enhancing cell bioenergetics in preclinical models may yield widespread favourable effects that could benefit persons with AD. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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“…On the other hand, it has been also demonstrated that mutations in the mtDNA exacerbate ROS production, contributing to disease onset and progression [98]. Moreover, alterations of the mitochondrial genome in neurodegeneration have been demonstrated also in terms of variation of copy number [99], that significantly varies in neurodegenerative diseases in respect to healthy controls, and has been proposed as an innovative biomarker [100][101][102][103]. This evidence supports the hypothesis that the mitochondrial genome significantly influences both pathological (e.g., neurodegeneration) and physiological processes (e.g., aging) [104].…”

Section: Mitochondria In Neurodegeneration: the Interplay Between Oximentioning

confidence: 99%

Mitochondrial DNA and Neurodegeneration: Any Role for Dietary Antioxidants?

Bordoni

Gabbianelli

2020

Antioxidants

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The maintenance of the mitochondrial function is essential in preventing and counteracting neurodegeneration. In particular, mitochondria of neuronal cells play a pivotal role in sustaining the high energetic metabolism of these cells and are especially prone to oxidative damage. Since overproduction of reactive oxygen species (ROS) is involved in the pathogenesis of neurodegeneration, dietary antioxidants have been suggested to counteract the detrimental effects of ROS and to preserve the mitochondrial function, thus slowing the progression and limiting the extent of neuronal cell loss in neurodegenerative disorders. In addition to their role in the redox-system homeostasis, mitochondria are unique organelles in that they contain their own genome (mtDNA), which acts at the interface between environmental exposures and the molecular triggers of neurodegeneration. Indeed, it has been demonstrated that mtDNA (including both genetics and, from recent evidence, epigenetics) might play relevant roles in modulating the risk for neurodegenerative disorders. This mini-review describes the link between the mitochondrial genome and cellular oxidative status, with a particular focus on neurodegeneration; moreover, it provides an overview on potential beneficial effects of antioxidants in preserving mitochondrial functions through the protection of mtDNA.

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Lower mitochondrial DNA content but not increased mutagenesis associates with decreased base excision repair activity in brains of AD subjects

Cited by 27 publications

References 66 publications

Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances

Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Mitochondrial DNA and Neurodegeneration: Any Role for Dietary Antioxidants?

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