Mitochondrial and Nuclear DNA Oxidative Damage in Physiological and Pathological Aging

Kowalska, Marta; Piekut, Thomas; Prendecki, Michał; Sodel, Agnieszka; Kozubski, Wojciech; Dorszewska, Jolanta

doi:10.1089/dna.2019.5347

Cited by 73 publications

(60 citation statements)

References 123 publications

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“…Mitochondrial DNA is more susceptible to ROS attack than nuclear DNA, because it is located in close proximity to the ROS generating electron transport chain. 35,36 Nuclear DNA damage is caused by mitochondrial derived ROS as well, but a substantial portion of DNA damage can be caused by free radical production from other sources. 35 Moreover, nuclear and mitochondrial oxidative damage lead to the activation of different repair and/or apoptosis-inducing pathways.…”

Section: J O U R N a L P R E -P R O O F Discussionmentioning

confidence: 99%

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Endothelial Endothelin Receptor A Expression Is Associated With Podocyte Injury and Oxidative Stress in Patients With Focal Segmental Glomerulosclerosis

Lest

Bakker

Dijkstra

et al. 2021

Kidney International Reports

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: J O U R N a L P R E -P R O O F Discussionmentioning

confidence: 99%

“…35 Moreover, nuclear and mitochondrial oxidative damage lead to the activation of different repair and/or apoptosis-inducing pathways. [36][37][38][39] Thus, targets of mitochondrial and nuclear oxidative DNA damage in disease may be different.…”

Section: J O U R N a L P R E -P R O O F Discussionmentioning

confidence: 99%

Endothelial Endothelin Receptor A Expression Is Associated With Podocyte Injury and Oxidative Stress in Patients With Focal Segmental Glomerulosclerosis

Lest

Bakker

Dijkstra

et al. 2021

Kidney International Reports

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“…Senescence is the gradual deterioration of cells or organs during aging [ 1 ]. The senescence processes have not yet been fully defined, but it is well-documented that oxidative damage plays a crucial rol [ 2 ]. Oxidative stress has also been associated with anxiety and cognitive disorders in older people [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Calcium Dobesilate Reverses Cognitive Deficits and Anxiety-Like Behaviors in the D-Galactose-Induced Aging Mouse Model through Modulation of Oxidative Stress

et al. 2021

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The long-term treatment of mice with D-galactose (D-gal) induces the overproduction of reactive oxygen species (ROS) and is a well-accepted experimental model of oxidative stress-linked cognitive disorders in physiological aging. Calcium dobesilate (CaD, Doxium®) is an established vasoactive and angioprotective drug commonly used for the clinical treatment of diabetic retinopathy and chronic venous insufficiency. It has antioxidant properties and controls vascular permeability. In the current study, we evaluated the protective effects of CaD (50 and 100 mg/kg/day p.o.) in male mice treated with D-gal (500 mg/kg/day p.o.) for six weeks. Results demonstrated that body weight loss, anxiety-like and cognitive impairments of D-gal-treated animals were reversed by CaD administration as evaluated by the measurement of mice performance in elevated plus-maze, Y-maze, and shuttle box tests. CaD treatment also inhibited the oxidative stress in aging mouse brains by decreasing malondialdehyde (MDA) levels and increasing superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) enzyme activities. These results could open new perspectives for the clinical use of CaD in treating and preventing cognitive impairment in older people.

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“…Impairment of protein import into the mitochondria extends beyond imported electron transport chain proteins, as the proteins required for maintenance of mitochondrial DNA (mtDNA) are also nuclear-encoded and likewise depend on the import machinery 26 . In addition, oxidative stress, whether toxicant or α-synuclein-induced, produces mtDNA damage 35 , which is known to elicit specific vulnerability to dopaminergic neurons 36,37 . The markers of mitochondrial dyshomeostasis observed within surviving cells following α-synuclein overexpression in this model suggests multiple, likely feed-forward, mechanisms surrounding mitochondrial protein import ultimately contribute to the death of dopaminergic neurons.…”

Section: Discussionmentioning

confidence: 99%

Protection from α-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20

Miranda

Rocha

Castro

et al. 2020

npj Parkinsons Dis.

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Dopaminergic neurons of the substantia nigra are selectively vulnerable to mitochondrial dysfunction, which is hypothesized to be an early and fundamental pathogenic mechanism in Parkinson’s disease (PD). Mitochondrial function depends on the successful import of nuclear-encoded proteins, many of which are transported through the TOM20–TOM22 outer mitochondrial membrane import receptor machinery. Recent data suggests that post-translational modifications of α-synuclein promote its interaction with TOM20 at the outer mitochondrial membrane and thereby inhibit normal protein import, leading to dysfunction, and death of dopaminergic neurons. As such, preservation of mitochondrial import in the face of α-synuclein accumulation might be a strategy to prevent dopaminergic neurodegeneration, however, this is difficult to assess using current in vivo models of PD. To this end, we established an exogenous co-expression system, utilizing AAV2 vectors to overexpress human α-synuclein and TOM20, individually or together, in the adult Lewis rat substantia nigra to assess whether TOM20 overexpression attenuates α-synuclein-induced dopaminergic neurodegeneration. Twelve weeks after viral injection, we observed that AAV2-TOM20 expression was sufficient to prevent loss of nigral dopaminergic neurons caused by AAV2-αSyn overexpression. The observed TOM20-mediated dopaminergic neuron preservation appeared to be due, in part, to the rescued expression (and presumed import) of nuclear-encoded mitochondrial electron transport chain proteins that were inhibited by α-synuclein overexpression. In addition, TOM20 overexpression rescued the expression of the chaperone protein GRP75/mtHSP70/mortalin, a stress-response protein involved in α-synuclein-induced injury. Collectively, these data indicate that TOM20 expression prevents α-synuclein-induced mitochondrial dysfunction, which is sufficient to rescue dopaminergic neurons in the adult rat brain.

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Mitochondrial and Nuclear DNA Oxidative Damage in Physiological and Pathological Aging

Cited by 73 publications

References 123 publications

Endothelial Endothelin Receptor A Expression Is Associated With Podocyte Injury and Oxidative Stress in Patients With Focal Segmental Glomerulosclerosis

Endothelial Endothelin Receptor A Expression Is Associated With Podocyte Injury and Oxidative Stress in Patients With Focal Segmental Glomerulosclerosis

Calcium Dobesilate Reverses Cognitive Deficits and Anxiety-Like Behaviors in the D-Galactose-Induced Aging Mouse Model through Modulation of Oxidative Stress

Protection from α-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20

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