C57BL/6J mice upregulate catalase to maintain the hydrogen peroxide buffering capacity of liver mitochondria

Dogar, Ibrahim; Dixon, Sarah Emily; Gill, Robert M.; Young, Adrian; Mallay, Sarah; Oldford, Catherine; Mailloux, Ryan J.

doi:10.1016/j.freeradbiomed.2019.10.409

Cited by 22 publications

(15 citation statements)

References 32 publications

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“…Therefore, it is advised that estimations of

/H 2 O 2 are conducted in the presence of inhibitors for the GSH, TRX, and catalase systems. Effective inhibitors for all three systems include 2,4-dinitrochlorobenzene (CDNB), auronofin (AF), and 3-Amino-1,2,4-triazole (3-AT), respectively [ 25 , 55 ]. Each individual inhibitor should be titrated into reaction chambers until maximal inhibition is reached, which is when the maximal rate of

/H 2 O 2 production has been reached.…”

Section: The Methodological Toolkit For Interrogating Individual Rates Of Ros Productionmentioning

confidence: 99%

“…Several studies have interrogated the hydroperoxide clearing capacity of mitochondria isolated from liver, skeletal muscle, and brain tissue from rodents and fish [ 55 , [74] , [75] , [76] ]. A complete list of inhibitors and substrate combinations that can be used to profile the clearance of hydroperoxides by isolated mitochondria is provide in Fig.…”

Section: Examining the H 2 O 2 Quenching Capacity If Mitochondriamentioning

confidence: 99%

“…Palmitoyl-CoA is an effective NNT inhibitor and has been successfully utilized to quantify its contribution towards H 2 O 2 degradation ( Fig. 3 ) [ 55 ]. The second option is the C57BL6J (6J) mouse strain, which harbors a loss-of-function mutation in the Nnt gene ( Fig.…”

Section: Examining the H 2 O 2 Quenching Capacity If Mitochondriamentioning

confidence: 99%

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An update on methods and approaches for interrogating mitochondrial reactive oxygen species production

Mailloux

2021

Redox Biology

Self Cite

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The chief ROS formed by mitochondria are superoxide ( ) and hydrogen peroxide (H 2 O 2 ). Superoxide is converted rapidly to H 2 O 2 and therefore the latter is the chief ROS emitted by mitochondria into the cell. Once considered an unavoidable by-product of aerobic respiration, H 2 O 2 is now regarded as a central mitokine used in mitochondrial redox signaling. However, it has been postulated that can also serve as a signal in mammalian cells. Progress in understanding the role of mitochondrial H 2 O 2 in signaling is due to significant advances in the development of methods and technologies for its detection. Unfortunately, the development of techniques to selectively measure basal changes has been met with more significant hurdles due to its short half-life and the lack of specific probes. The development of sensitive techniques for the selective and real time measure of and H 2 O 2 has come on two fronts: development of genetically encoded fluorescent proteins and small molecule reporters. In 2015, I published a detailed comprehensive review on the state of knowledge for mitochondrial ROS production and how it is controlled, which included an in-depth discussion of the up-to-date methods utilized for the detection of both superoxide ( ) and H 2 O 2 . In the article, I presented the challenges associated with utilizing these probes and their significance in advancing our collective understanding of ROS signaling. Since then, many other authors in the field of Redox Biology have published articles on the challenges and developments detecting and H 2 O 2 in various organisms [ [1] , [2] , [3] ]. There has been significant advances in this state of knowledge, including the development of novel genetically encoded fluorescent H 2 O 2 probes, several sensors, and the establishment of a toolkit of inhibitors and substrates for the interrogation of mitochondrial H 2 O 2 production and the antioxidant defenses utilized to maintain the cellular H 2 O 2 steady-state. Here, I provide an update on these methods and their implementation in furthering our understanding of how mitochondria serve as cell ROS stabilizing devices for H 2 O 2 signaling.

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“…Therefore, it is advised that estimations of

/H 2 O 2 production has been reached.…”

Section: The Methodological Toolkit For Interrogating Individual Rates Of Ros Productionmentioning

confidence: 99%

Section: Examining the H 2 O 2 Quenching Capacity If Mitochondriamentioning

confidence: 99%

Section: Examining the H 2 O 2 Quenching Capacity If Mitochondriamentioning

confidence: 99%

See 1 more Smart Citation

An update on methods and approaches for interrogating mitochondrial reactive oxygen species production

Mailloux

2021

Redox Biology

Self Cite

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“…Although in some studies CPI-613 elicited a ROS burst, other research groups use CPI-613 as a ROS-minimizing agent in other models and conditions [ 204 , 205 ]. In general, CPI-613 is applied as either a PDC or KGDH inhibitor in yeast, cell culture or murine experiments [ 206 , 207 , 208 , 209 , 210 ]. It is important to note that metabolite and carbon source availability are mediating the cytotoxicity of CPI-613 in cell culture experiments [ 193 , 194 ].…”

Section: The Lipoic Acid Derivative Cpi-613 In Cancer Therapymentioning

confidence: 99%

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Neitzel

Demuth

Wittmann

et al. 2020

Cancers

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Colorectal cancer (CRC) is among the most frequent cancer entities worldwide. Multiple factors are causally associated with CRC development, such as genetic and epigenetic alterations, inflammatory bowel disease, lifestyle and dietary factors. During malignant transformation, the cellular energy metabolism is reprogrammed in order to promote cancer cell growth and proliferation. In this review, we first describe the main alterations of the energy metabolism found in CRC, revealing the critical impact of oncogenic signaling and driver mutations in key metabolic enzymes. Then, the central role of mitochondria and the tricarboxylic acid (TCA) cycle in this process is highlighted, also considering the metabolic crosstalk between tumor and stromal cells in the tumor microenvironment. The identified cancer-specific metabolic transformations provided new therapeutic targets for the development of small molecule inhibitors. Promising agents are in clinical trials and are directed against enzymes of the TCA cycle, including isocitrate dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase (KGDH). Finally, we focus on the α-lipoic acid derivative CPI-613, an inhibitor of both PDC and KGDH, and delineate its anti-tumor effects for targeted therapy.

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“…Recent studies indicate that isolated mitochondria from C57Bl/6N mice that contain NNT are reliant on the glutathione and thioredoxin systems to clear exogenously added H 2 O 2 [ 50 ]. However, it is unclear if pathophysiological production of mitochondrial ROS has any impact on the regulation of NNT.…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide nucleotide transhydrogenase (NNT) regulates mitochondrial ROS and endothelial dysfunction in response to angiotensin II

et al. 2020

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Endothelial dysfunction is a critical, initiating step in the development of hypertension (HTN) and mitochondrial reactive oxygen species (ROS) are important contributors to endothelial dysfunction. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in the nicotinamide nucleotide transhydrogenase ( Nnt ) gene that are associated with endothelial dysfunction and increased risk for HTN. NNT is emerging as an important enzyme that regulates mitochondrial NADPH levels and mitochondrial redox balance by supporting the thiol dependent peroxidase systems in the mitochondria. We have previously shown that the absence of NNT in C57Bl/6J animals promotes a more severe hypertensive phenotype through reductions in • NO and endothelial dependent vessel dilation. However, the impact of NNT on human endothelial cell function remains unclear. We utilized NNT directed shRNA in human aortic endothelial cells to test the hypothesis that NNT critically regulates mitochondrial redox balance and endothelial function in response to angiotensin II (Ang II). We demonstrate that NNT expression and activity are elevated in response to the mitochondrial dysfunction and oxidative stress associated with Ang II treatment. Knockdown of NNT led to a significant elevation of mitochondrial ROS production and impaired glutathione peroxidase and glutathione reductase activities associated with a reduction in the NADPH/NADP + ratio. Loss of NNT also promoted mitochondrial dysfunction, disruption of the mitochondrial membrane potential, and impaired ATP production in response to Ang II. Finally, we observed that, while the loss of NNT augmented eNOS phosphorylation at Ser 1177 , neither eNOS activity nor nitric oxide production were similarly increased. The results from these studies clearly demonstrate that NNT is critical for the maintenance of mitochondrial redox balance and mitochondrial function. Loss of NNT and disruption of redox balance leads to oxidative stress that compromises eNOS activity that could have a profound effect on the endothelium dependent regulation of vascular tone.

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C57BL/6J mice upregulate catalase to maintain the hydrogen peroxide buffering capacity of liver mitochondria

Cited by 22 publications

References 32 publications

An update on methods and approaches for interrogating mitochondrial reactive oxygen species production

An update on methods and approaches for interrogating mitochondrial reactive oxygen species production

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Nicotinamide nucleotide transhydrogenase (NNT) regulates mitochondrial ROS and endothelial dysfunction in response to angiotensin II

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