Deficiency of Mitochondrial Functions and Peroxidation of Frontoparietal Cortex Enhance Isoflurane Sensitivity in Aging Mice

Background: Hypersensitivity to general anesthetics may predict poor postoperative outcomes, especially among the older subjects. Therefore, it is essential to elucidate the mechanism underlying hypersensitivity to volatile anesthetics in the aging population. Given the fact that isoflurane sensitivity increases with aging, we hypothesized that deficiencies of mitochondrial function and elevated oxidative levels in the frontoparietal cortex may contribute to the enhanced sensitivity to isoflurane in aging mice.Methods: Isoflurane sensitivity in aging mice was determined by the concentration of isoflurane that is required for loss of righting reflex (LORR). Mitochondrial bioenergetics of the frontoparietal cortex was measured using a Seahorse XFp analyzer. Protein oxidation and lipid oxidation in the frontoparietal cortex were assessed using the Oxyblot protein oxidation detection kit and thiobarbituric acid reactive substance (TBARS) assay, respectively. Contributions of mitochondrial complex II inhibition by malonate and peroxidation by ozone to isoflurane sensitivity were tested in vivo. Besides, effects of antioxidative therapy on mitochondrial function and isoflurane sensitivity in mice were also measured.Results: The mean concentration of isoflurane that is required for LORR in aging mice (14–16 months old) was 0.83% ± 0.13% (mean ± SD, n = 80). Then, the mice were divided into three groups as sensitive group (S group, mean − SD), medium group (M group), and resistant group (R group, mean + SD) based on individual concentrations of isoflurane required for LORR. Activities of mitochondrial complex II and complex IV in mice of the S group were significantly lower than those of the R group, while frontoparietal cortical malondialdehyde (MDA) levels were higher in the mice of S group. Both inhibition of mitochondrial complexes and peroxidation significantly decreased the concentration of isoflurane that is required for LORR in vivo. After treatment with idebenone, the levels of lipid oxidation were alleviated and mitochondrial function was restored in aging mice. The concentration of isoflurane that required for LORR was also elevated after idebenone treatment.Conclusions: Decreased mitochondrial functions and higher oxidative stress levels in the frontoparietal cortex may contribute to the hypersensitivity to isoflurane in aging mice.

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The Nitrone Disodium 2,4-Sulphophenyl-N-Tert-Butylnitrone is Without Cytoprotective Effect on Sodium Nitroprusside-Induced Cell Death in N1E-115 Neuroblastoma Cells in vitro

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600517 ◽

2007 ◽

Vol 28 (1) ◽

pp. 24-28 ◽

Cited By ~ 13

Author(s):

Atticus H Hainsworth ◽

Nasrin Bhuiyan ◽

A Richard Green

Keyword(s):

Cell Death ◽

Free Radical ◽

Sodium Nitroprusside ◽

Neurovascular Unit ◽

Neuroblastoma Cells ◽

Mitochondrial Complex ◽

Complex Ii ◽

Radical Trapping

Disodium 2,4-sulphophenyl- N-tert-butylnitrone (NXY-059) is a novel free radical-trapping compound that is neuroprotective in both rodent and primate models of acute ischaemic stroke. Neuroprotection in vitro by NXY-059 has not been reported previously, and we have now investigated whether such an effect can be detected using a simple cell culture model of neurotoxicity. Neuron-like cells of the neuroblastoma-derived clonal cell line N1E-115 were exposed to the free radical-generating agent sodium nitroprusside (SNP), which produced a concentration-dependent reduction in mitochondrial complex II activity 24 h later (EC50 approximately 100 micromolar). Cell death induced by SNP (100 micromolar), assessed either by an increased proportion of apoptotic nuclear morphology or by mitochondrial complex II activity, was inhibited by a cocktail of known antioxidants (ascorbate, reduced glutathione, and dithiothreitol, all at 100 micromolar) but not by NXY-059 at a concentration known to be neuroprotective in vivo (300 micromolar). Disodium 2,4-sulphophenyl- N-tert-butylnitrone was also without effect on H2O2-mediated cytotoxicity. These results support recent data suggesting that in vivo NXY-059 probably acts at the neurovascular unit rather than at an intracellular site as a neuroprotective agent.

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Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0408487101 ◽

2004 ◽

Vol 102 (1) ◽

pp. 244-249 ◽

Cited By ~ 181

Author(s):

M. J. Calkins ◽

R. J. Jakel ◽

D. A. Johnson ◽

K. Chan ◽

Y. W. Kan ◽

...

Keyword(s):

Mitochondrial Complex ◽

Complex Ii

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Dietary Polyphenols and Mitochondrial Function: Role in Health and Disease

Current Medicinal Chemistry ◽

10.2174/0929867324666170529101810 ◽

2019 ◽

Vol 26 (19) ◽

pp. 3376-3406 ◽

Cited By ~ 19

Author(s):

José Teixeira ◽

Daniel Chavarria ◽

Fernanda Borges ◽

Lech Wojtczak ◽

Mariusz R. Wieckowski ◽

...

Keyword(s):

Mitochondrial Function ◽

Redox Status ◽

Dietary Polyphenols ◽

Beneficial Effects ◽

Regulatory Processes ◽

In Vivo Experiments ◽

Mitochondrial Functions ◽

Huge Impact

Mitochondria are cytoplasmic double-membraned organelles that are involved in a myriad of key cellular regulatory processes. The loss of mitochondrial function is related to the pathogenesis of several human diseases. Over the last decades, an increasing number of studies have shown that dietary polyphenols can regulate mitochondrial redox status, and in some cases, prevent or delay disease progression. This paper aims to review the role of four dietary polyphenols – resveratrol, curcumin, epigallocatechin-3-gallate nd quercetin – in molecular pathways regulated by mitochondria and their potential impact on human health. Cumulative evidence showed that the aforementioned polyphenols improve mitochondrial functions in different in vitro and in vivo experiments. The mechanisms underlying the polyphenols’ beneficial effects include, among others, the attenuation of oxidative stress, the regulation of mitochondrial metabolism and biogenesis and the modulation of cell-death signaling cascades, among other mitochondrial-independent effects. The understanding of the chemicalbiological interactions of dietary polyphenols, namely with mitochondria, may have a huge impact on the treatment of mitochondrial dysfunction-related disorders.

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Mitochondrial Complex II In Intestinal Epithelial Cells Regulates T-cell Mediated Immunopathology

10.1101/2020.03.12.978692 ◽

2020 ◽

Author(s):

Hideaki Fujiwara ◽

Anna V Mathew ◽

Ilya Kovalenko ◽

Anupama Pal ◽

Ho-Joon Lee ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Critical Role ◽

Clinical Samples ◽

Intestinal Damage ◽

Intestinal Epithelial ◽

Mitochondrial Complex ◽

In Vivo Models ◽

Complex Ii

SummaryIntestinal epithelial cell (IEC) damage by T cells contributes to alloimmune, autoimmune and iatrogenic diseases such as graft-versus-host disease (GVHD), inflammatory bowel disease (IBD) and immune checkpoint blockade (ICB) mediated colitis, respectively. Despite significant advances in understanding the aberrant biology of T cells in these diseases, little is known about how the fundamental biological processes of the target IECs influence the disease severity. Here, through analyses of metabolic pathways of IECs, we identified disruption of oxidative phosphorylation without a concomitant change in glycolysis and an increase in succinate levels in several distinct in vivo models of T cell mediated gastrointestinal damage such as GVHD, IBD and ICB mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses identified a critical role for IEC intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations that contributed to the severity of intestinal damage. The critical mechanistic role of IEC intrinsic SDHA was confirmed by complementary chemical and genetic reduction of SDHA and with IEC specific deletion of SDHA. Further in vitro and in vivo mechanistic studies demonstrated that loss of SDHA in IECs was mediated by the perforin-granzyme from the T cells. The loss of SDHA was also validated in human clinical samples. These data identify a critical role for the alteration of the IEC specific mitochondrial complex II component SDHA in the regulation of the severity of T cell mediated intestinal diseases.

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Schisandrin Restores the Amyloid β-Induced Impairments on Mitochondrial Function, Energy Metabolism, Biogenesis, and Dynamics in Rat Primary Hippocampal Neurons

Pharmacology ◽

10.1159/000507818 ◽

2021 ◽

pp. 1-11

Author(s):

Zhongyuan Piao ◽

Lin Song ◽

Lifen Yao ◽

Limei Zhang ◽

Yichan Lu

Keyword(s):

Energy Metabolism ◽

Cytochrome C ◽

Mitochondrial Biogenesis ◽

Mitochondrial Function ◽

Hippocampal Neurons ◽

Citrate Synthase ◽

Mitochondrial Permeability Transition ◽

Amyloid Β ◽

Mitochondrial Functions ◽

Primary Hippocampal Neurons

Introduction: Schisandrin which is derived from Schisandra chinensis has shown multiple pharmacological effects on various diseases including Alzheimer’s disease (AD). It is demonstrated that mitochondrial dysfunction plays an essential role in the pathogenesis of neurodegenerative disorders. Objective: Our study aims to investigate the effects of schisandrin on mitochondrial functions and metabolisms in primary hippocampal neurons. Methods: In our study, rat primary hippocampal neurons were isolated and treated with indicated dose of amyloid β1–42 (Aβ1–42) oligomer to establish a cell model of AD in vitro. Schisandrin (2 μg/mL) was further subjected to test its effects on mitochondrial function, energy metabolism, mitochondrial biogenesis, and dynamics in the Aβ1–42 oligomer-treated neurons. Results and Conclusions: Our findings indicated that schisandrin significantly alleviated the Aβ1–42 oligomer-induced loss of mitochondrial membrane potential and impaired cytochrome c oxidase activity. Additionally, the opening of mitochondrial permeability transition pore and release of cytochrome c were highly restricted with schisandrin treatment. Alterations in cell viability, ATP production, citrate synthase activity, and the expressions of glycolysis-related enzymes demonstrated the relief of defective energy metabolism in Aβ-treated neurons after the treatment of schisandrin. For mitochondrial biogenesis, elevated expression of peroxisome proliferator-activated receptor γ coactivator along with promoted mitochondrial mass was found in schisandrin-treated cells. The imbalance in the cycle of fusion and fission was also remarkably restored by schisandrin. In summary, this study provides novel mechanisms for the protective effect of schisandrin on mitochondria-related functions.

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Poor Mitochondrial Health and Systemic Inflammation? Testing of a Classical Hypothesis

Innovation in Aging ◽

10.1093/geroni/igaa057.416 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 126-127

Author(s):

Marta Zampino ◽

Luigi Ferrucci ◽

Richard Spencer ◽

Kenneth Fishbein ◽

Eleanor Simonsick ◽

...

Keyword(s):

Mitochondrial Function ◽

Fat Body ◽

Reference Group ◽

Linear Regression Analysis ◽

Oxidative Capacity ◽

Conclusive Evidence ◽

Resonance Spectroscopy ◽

Low Grade ◽

Severe Impairment

Abstract Chronic low-grade inflammation often occurs with aging and has been associated with negative health outcomes. Despite extensive research on the origins of “inflammaging”, the causative mechanisms remain unclear. However, a connection between poor mitochondrial health and chronic inflammation has been hypothesized, with decreasing mitochondrial function occurring with age and precipitating an increase in reactive oxygen species and other pro-inflammatory macromolecules such as mitochondrial DNA. We tested this hypothesis on a population of 619 subjects from the Baltimore Longitudinal Study of Aging, measuring muscle mitochondrial oxidative capacity in vivo by phosphorus magnetic resonance spectroscopy (P-MRS), and plasma interleukin (IL)-6, the most widely used biomarker of inflammaging. The P-MRS-derived post-exercise phosphocreatine recovery time constant tau-PCr, a measure of oxidative capacity, was expressed as a categorical variable through assignment to quintiles. Participants in the first quintile of tau-PCr (best mitochondrial function) were taken as reference and compared to the others using linear regression analysis adjusted for sex, age, lean and fat body mass, and physical activity. Those participants with the lowest oxidative capacity had significantly higher log(IL-6) levels as compared to the reference group. However, data from the other quintiles was not significantly different from the reference values. In conclusion, severe impairment of oxidative capacity is associated with increased inflammation. This study design does not provide conclusive evidence of whether increased inflammation and impaired bioenergetic recovery are both caused by underlying poor health status, or whether mitochondrial deficits lead directly to the observed inflammation; we anticipate addressing this important question with longitudinal studies.

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Mitochondrial complex I abnormalities is associated with tau and clinical symptoms in mild Alzheimer’s disease

Molecular Neurodegeneration ◽

10.1186/s13024-021-00448-1 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Tatsuhiro Terada ◽

Joseph Therriault ◽

Min Su Peter Kang ◽

Melissa Savard ◽

Tharick Ali Pascoal ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Dysfunction ◽

Complex I ◽

Clinical Symptoms ◽

Mitochondrial Complex I ◽

Braak Stage ◽

Mitochondrial Complex ◽

Temporal Area

Abstract Background Mitochondrial electron transport chain abnormalities have been reported in postmortem pathological specimens of Alzheimer’s disease (AD). However, it remains unclear how amyloid and tau are associated with mitochondrial dysfunction in vivo. The purpose of this study is to assess the local relationships between mitochondrial dysfunction and AD pathophysiology in mild AD using the novel mitochondrial complex I PET imaging agent [18F]BCPP-EF. Methods Thirty-two amyloid and tau positive mild stage AD dementia patients (mean age ± SD: 71.1 ± 8.3 years) underwent a series of PET measurements with [18F]BCPP-EF mitochondrial function, [11C]PBB3 for tau deposition, and [11C] PiB for amyloid deposition. Age-matched normal control subjects were also recruited. Inter and intrasubject comparisons of levels of mitochondrial complex I activity, amyloid and tau deposition were performed. Results The [18F]BCPP-EF uptake was significantly lower in the medial temporal area, highlighting the importance of the mitochondrial involvement in AD pathology. [11C]PBB3 uptake was greater in the temporo-parietal regions in AD. Region of interest analysis in the Braak stage I-II region showed significant negative correlation between [18F]BCPP-EF SUVR and [11C]PBB3 BPND (R = 0.2679, p = 0.04), but not [11C] PiB SUVR. Conclusions Our results indicated that mitochondrial complex I is closely associated with tau load evaluated by [11C]PBB3, which might suffer in the presence of its off-target binding. The absence of association between mitochondrial complex I dysfunction with amyloid load suggests that mitochondrial dysfunction in the trans-entorhinal and entorhinal region is a reflection of neuronal injury occurring in the brain of mild AD.

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ApoE4 (Δ272–299) induces mitochondrial‐associated membrane formation and mitochondrial impairment by enhancing GRP75-modulated mitochondrial calcium overload in neuron

Cell & Bioscience ◽

10.1186/s13578-021-00563-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Tao Liang ◽

Weijian Hang ◽

Jiehui Chen ◽

Yue Wu ◽

Bin Wen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Calcium Transport ◽

Calcium Overload ◽

Mitochondrial Calcium ◽

Mitochondrial Impairment

Abstract Background Apolipoprotein E4 (apoE4) is a major genetic risk factor of Alzheimer’s disease. Its C-terminal-truncated apoE4 (Δ272–299) has neurotoxicity by affecting mitochondrial respiratory function. However, the molecular mechanism(s) underlying the action of apoE4 (Δ272–299) in mitochondrial function remain poorly understood. Methods The impact of neuronal apoE4 (Δ272–299) expression on ER stress, mitochondrial-associated membrane (MAM) formation, GRP75, calcium transport and mitochondrial impairment was determined in vivo and in vitro. Furthermore, the importance of ER stress or GRP75 activity in the apoE4 (Δ272–299)-promoted mitochondrial dysfunction in neuron was investigated. Results Neuronal apoE4 (Δ272–299) expression induced mitochondrial impairment by inducing ER stress and mitochondrial-associated membrane (MAM) formation in vivo and in vitro. Furthermore, apoE4 (Δ272–299) expression promoted GRP75 expression, mitochondrial dysfunction and calcium transport into the mitochondria in neuron, which were significantly mitigated by treatment with PBA (an inhibitor of ER stress), MKT077 (a specific GRP75 inhibitor) or GRP75 silencing. Conclusions ApoE4 (Δ272–299) significantly impaired neuron mitochondrial function by triggering ER stress, up-regulating GRP75 expression to increase MAM formation, and mitochondrial calcium overload. Our findings may provide new insights into the neurotoxicity of apoE4 (Δ272–299) against mitochondrial function and uncover new therapeutic targets for the intervention of Alzheimer’s disease.

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