2020
DOI: 10.1021/acs.jproteome.9b00861
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Oxidative Damage to the TCA Cycle Enzyme MDH1 Dysregulates Bioenergetic Enzymatic Activity in the Aged Murine Brain

Abstract: Aging can have profound effects on the mammalian brain leading to neurodegeneration and cognitive impairment. The brain has exceptionally highenergy requirements and is particularly susceptible to damage within its bioenergetic pathways. Here, we asked how the bioenergetic proteome of the murine brain changed with age and how this might affect brain function. Using label-free LC-MS/ MS proteomics for the discovery phase and quantitative multiple reaction monitoring LC-MRM-MS/MS for the validation phase, we fou… Show more

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Cited by 24 publications
(33 citation statements)
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References 45 publications
(71 reference statements)
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“…These metabolic impairments contribute to and can be driven by chronic generation of surplus ROS that overwhelm antioxidant defenses and transform otherwise hormetic ROS into drivers of metabolic failure ( Grimm and Eckert, 2017 ; Guo et al, 2020 ). KEGG and GO enrichment suggests decreased activity of antioxidant systems in both these neuron types.…”
Section: Discussionmentioning
confidence: 99%
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“…These metabolic impairments contribute to and can be driven by chronic generation of surplus ROS that overwhelm antioxidant defenses and transform otherwise hormetic ROS into drivers of metabolic failure ( Grimm and Eckert, 2017 ; Guo et al, 2020 ). KEGG and GO enrichment suggests decreased activity of antioxidant systems in both these neuron types.…”
Section: Discussionmentioning
confidence: 99%
“…The aforementioned shift from aerobic to anaerobic use of glucose-derived pyruvate due to decreased PHD activity in aging rat brain is hypothesized to be in response to increased H 2 O 2 production in NADH-depleted mitochondria ( Zhou et al, 2008 , 2009 ). Furthermore, oxidative damage has been shown to impair activity of numerous TCA enzymes, such as isocitrate dehydrogenase and aconitase, in many aging models ( Das et al, 2001 ; Schriner et al, 2005 ; Di Domenico et al, 2010 ; Hastings et al, 2019 ; Guo et al, 2020 ). Both of these enzymes are also downregulated in PVC and BSC with age ( Figure 9 ).…”
Section: Discussionmentioning
confidence: 99%
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“…Proteomics analysis found that the dysregulation of TCA enzyme levels during aging includes the upregulation of malate dehydrogenase 1 (MDH1), fumarate dehydrogenase 1 (FH1), and subunits of NADH dehydrogenase, succinate dehydrogenase, and pyruvate dehydrogenase (PDH). Impaired TCA cycle metabolism is also associated with the downregulation of ICDH 1/2 and a subunit of succinyl-CoA ligase in the brains of aged mouse brains (Guo et al, 2020). Furthermore, a reduction in the metabolites from the TCA cycle has been measured in both aging and AD mouse models, while increases in the levels of the ceramides and sphingosine-1 phosphate (i.e., inflammatory metabolites) occurred in the aging group.…”
Section: Altered Tca Cycle and Oxphos In Aging And Admentioning
confidence: 98%
“…Numerous recent studies have shown that biomolecule damage by spontaneous chemical reactions (i.e. degenerative protein modifications; DPMs) as a major contributor to age-linked diseases 13-16,41-44 . We have previously reported that specific matrix proteins in carotid atherosclerotic plaque from CVD patients exhibit marked deamidation of NGR motifs 5 , thus facilitating increased leukocyte binding to core matrix components 7 .…”
Section: Discussionmentioning
confidence: 99%