Glutathione maintenance mitigates age-related susceptibility to redox cycling agents

Thomas, Nicholas O.; Shay, Kate Petersen; Kelley, Amanda; Butler, Jane; Hagen, Tory M.

doi:10.1016/j.redox.2016.09.010

Cited by 19 publications

(17 citation statements)

References 101 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5 j). This metabolite decreased across ages in Ctrl mice, but did not change across age in AD mice, suggesting that glutathione is specifically related to ARCD 46 . In addition, all of the changed metabolites are implicated in protein synthesis and oxidative stress, both of which have been implicated in AD pathology 47 , 48 .…”

Section: Resultsmentioning

confidence: 84%

Divergence in the metabolome between natural aging and Alzheimer’s disease

Hunsberger

Greenwood

Tolstikov

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a progressive and debilitating neurodegenerative disorder and one of the leading causes of death in the United States. Although amyloid plaques and fibrillary tangles are hallmarks of AD, research suggests that pathology associated with AD often begins 20 or more years before symptoms appear. Therefore, it is essential to identify early-stage biomarkers in those at risk for AD and age-related cognitive decline (ARCD) in order to develop preventative treatments. Here, we used an untargeted metabolomics analysis to define system-level alterations following cognitive decline in aged and APP/PS1 (AD) mice. At 6, 12, and 24 months of age, both control (Ctrl) and AD mice were tested in a 3-shock contextual fear conditioning (CFC) paradigm to assess memory decline. AD mice exhibited memory deficits across age and these memory deficits were also seen in naturally aged mice. Prefrontal cortex (PFC), hippocampus (HPC), and spleen were then collected and analyzed for metabolomic alterations. A number of significant pathways were altered between Ctrl and AD mice and naturally aged mice. By identifying systems-level alterations following ARCD and AD, these data could provide insights into disease mechanisms and advance the development of biomarker panels. Alzheimer's disease (AD), a progressive and debilitating neurodegenerative disorder, characterized by senile amyloid plaques and tau fibrillary tangles, is the leading cause of dementia 1. Amyloid plaques are aggregates of various amyloid peptides derived from the amyloid precursor protein (APP). APP accumulates when presenilin 1 and 2 mutant genes (PS1 and PS2) enhance the γ-secretase-mediated processing of APP 2. Therefore, we have chosen the APP/PS1 AD mouse model to best replicate the human amyloid cascade. This amyloid accumulation then promotes the spread of tau tangles, consisting of hyperphosphorylated tau protein, inevitably leading to cognitive decline 3. However, research suggests that the pathology associated with AD often begins 20 or more years before symptoms appear 4 , which makes this a critical time window for possible preventative treatments. Because aging is the greatest risk factor for developing AD 5 , it is also important to examine age-related brain changes and age-related cognitive decline (ARCD). ARCD is a normal process of aging where conceptual reasoning, memory, and processing speed gradually decline over time (fluid intelligence) 6-8. However, ARCD differs from AD in that certain abilities, such as vocabulary or other skills that have accumulated throughout life, are resilient to brain aging (crystallized intelligence) 9. It is important to understand how metabolites influence ARCD and AD, as our current aging population is expected to double in the next 40 years 10. One of the biggest problems facing AD research is the lack of biomarkers for diagnosis and treatment. Currently, there are only 3 FDA-approved diagnostic tests for AD, all of which are positron emission tomography (PET) neuroimaging scans for amyloid 11-1...

show abstract

Section: Resultsmentioning

confidence: 84%

Divergence in the metabolome between natural aging and Alzheimer’s disease

Hunsberger

Greenwood

Tolstikov

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…In a prior study, we established that hepatocytes from old rats were nearly 50% more susceptible to menadione (LC 50 young: 405 μM; old: 275 μM) with significant differences in GSH loss and increased markers of lipid peroxidation within minutes [25]. To determine whether the enhanced toxicity from menadione insult was mediated at least in part through mitochondrial dysfunction, we treated hepatocytes isolated from young and old F344 rats with 300 μM menadione (the ∼LC 50 for old) and assayed mGSH levels over a 20 min time-course.…”

Section: Resultsmentioning

confidence: 99%

“…Menadione is a potent redox cycling compound that generates a strong, persistent oxidative stress via the initial generation of superoxide followed by its dismutation into more deleterious ROS/RNS [26,54]. We have previously demonstrated that the age-related increase in vulnerability to acute challenge with this compound is GSH-dependent [25]. Additionally, menadione treatment in isolated mitochondria was previously demonstrated to deplete GSH and inhibit Complex I activity [27,55].…”

Section: Discussionmentioning

confidence: 99%

“…While the age-related loss of mGSH may be attributable to a variety of factors such as changes in membrane fluidity, decreased transport, or greater GSH utilization due to an increasingly oxidant-rich environment, our lab showed that hepatocellular GSH synthesis declines with age, which may also significantly alter mGSH levels [4]. In this regard, we showed that declines in Nrf2-dependent expression of GSH synthesis enzymes limited the basal GSH synthesis capacity and sensitized hepatocytes from old rats to acute administration of menadione, a redox cycling agent [25]. Specifically, decreased basal levels of GSH and the GSH-dependent lipid peroxidase, GPx4, led to an increased rate and magnitude of lipid peroxidation and a concomitant loss in cell viability.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Age-related loss of mitochondrial glutathione exacerbates menadione-induced inhibition of Complex I

2019

Self Cite

View full text Add to dashboard Cite

The role of mitochondrial GSH (mGSH) in the enhanced age-related susceptibility to xenobiotic toxicity is not well defined. We determined mGSH status and indices of mitochondrial bioenergetics in hepatocytes from young and old F344 rats treated with 300 μM menadione, a concentration that causes 50% cell death in old. At this concentration, mGSH was significantly lost only in hepatocytes from old rats, and with near total depletion due to lower basal mGSH in aged cells. In old hepatocytes, menadione caused mitochondrial membrane potential to collapse, as well as significant deficits in maximal O 2 consumption and respiratory reserve capacity, indicators of cellular bioenergetic resiliency. Further examination revealed that the menadione-mediated loss of respiratory reserve capacity in aged hepatocytes was from significant inhibition of Complex I activity and increased proton leak, for which an increase in Complex II activity was not able to compensate. These data demonstrate an age-related increase in mitochondrial susceptibility to a redox-cycling challenge, particularly in regards to Complex I activity, and provide a plausible mechanism to link this vulnerability to mGSH perturbations.

show abstract

“…A major hallmark of aging, and a key driver for the onset of age-related pathophysiologies is the disruption of cellular redox homeostatic mechanisms that protect against environmental factors, such as oxidative, pathological, and toxicological insults [ 25 ]. During aging, weakened antioxidant defenses allow the accumulation of toxic reactive oxygen species that contribute to aging and to the onset of multiple diseases [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress and Effect of Treatment on the Oxidation Product Decomposition Processes in IBD

Dudzińska

Gryzińska

Ognik

et al. 2018

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Oxidative stress plays an important role in IBD because chronic intestinal inflammation is associated with the overproduction of reactive oxygen species (ROS) leading to oxidative stress, which has been implicated in IBD. Many lines of evidence suggest that IBD is associated with an imbalance between ROS and antioxidant activity which generates oxidative stress as the result of either ROS overproduction or a decrease in antioxidant activity. Our study was to evaluate the influence of oxidative stress and antioxidants on the course of the disease and treatment of IBD patients. Our results show that an increase of LOOH levels positively correlates with an increase in MDA levels; therefore, MDA may be a marker indicating lipid peroxidation. Also, being the decomposition product of oxidation processes, MDA may be applied as a useful biomarker for identifying the effect of endogenous oxidative stress in Crohn's disease patients. The anti-inflammatory efficacy of AZA drugs may be the result of a reduction of the amount of lipid peroxides in the intestinal mucosa cells in CD patients and facilitate mucosal healing.

show abstract

Glutathione maintenance mitigates age-related susceptibility to redox cycling agents

Cited by 19 publications

References 101 publications

Divergence in the metabolome between natural aging and Alzheimer’s disease

Divergence in the metabolome between natural aging and Alzheimer’s disease

Age-related loss of mitochondrial glutathione exacerbates menadione-induced inhibition of Complex I

Oxidative Stress and Effect of Treatment on the Oxidation Product Decomposition Processes in IBD

Contact Info

Product

Resources

About