scholarly journals Neuronal metabolic rewiring promotes resilience to neurodegeneration caused by mitochondrial dysfunction

2020 ◽  
Vol 6 (35) ◽  
pp. eaba8271 ◽  
Author(s):  
E. Motori ◽  
I. Atanassov ◽  
S. M. V. Kochan ◽  
K. Folz-Donahue ◽  
V. Sakthivelu ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Tricarboxylic Acid Cycle ◽  
Mitochondrial Fusion ◽  
Metabolic Plasticity ◽  
Sequential Activation ◽  
End Stage ◽  
Tricarboxylic Acid Cycle Intermediates ◽  
Disease Stages

Neurodegeneration in mitochondrial disorders is considered irreversible because of limited metabolic plasticity in neurons, yet the cell-autonomous implications of mitochondrial dysfunction for neuronal metabolism in vivo are poorly understood. Here, we profiled the cell-specific proteome of Purkinje neurons undergoing progressive OXPHOS deficiency caused by disrupted mitochondrial fusion dynamics. We found that mitochondrial dysfunction triggers a profound rewiring of the proteomic landscape, culminating in the sequential activation of precise metabolic programs preceding cell death. Unexpectedly, we identified a marked induction of pyruvate carboxylase (PCx) and other anaplerotic enzymes involved in replenishing tricarboxylic acid cycle intermediates. Suppression of PCx aggravated oxidative stress and neurodegeneration, showing that anaplerosis is protective in OXPHOS-deficient neurons. Restoration of mitochondrial fusion in end-stage degenerating neurons fully reversed these metabolic hallmarks, thereby preventing cell death. Our findings identify a previously unappreciated pathway conferring resilience to mitochondrial dysfunction and show that neurodegeneration can be reversed even at advanced disease stages.

scholarly journals In Vivo Microdialysis of Endogenous and 13C-labeled TCA Metabolites in Rat Brain: Reversible and Persistent Effects of Mitochondrial Inhibition and Transient Cerebral Ischemia

Metabolites ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 204 ◽  
Author(s):  
Jesper F. Havelund ◽  
Kevin H. Nygaard ◽  
Troels H. Nielsen ◽  
Carl-Henrik Nordström ◽  
Frantz R. Poulsen ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Mitochondrial Dysfunction ◽  
Rat Brain ◽  
De Novo ◽  
Tricarboxylic Acid Cycle ◽  
Experimental Models ◽  
Transient Cerebral Ischemia ◽  
Metabolic Disturbances ◽  
Metabolic Marker

Cerebral micro-dialysis allows continuous sampling of extracellular metabolites, including glucose, lactate and pyruvate. Transient ischemic events cause a rapid drop in glucose and a rise in lactate levels. Following such events, the lactate/pyruvate (L/P) ratio may remain elevated for a prolonged period of time. In neurointensive care clinics, this ratio is considered a metabolic marker of ischemia and/or mitochondrial dysfunction. Here we propose a novel, sensitive microdialysis liquid chromatography-mass spectrometry (LC-MS) approach to monitor mitochondrial dysfunction in living brain using perfusion with 13C-labeled succinate and analysis of 13C-labeled tricarboxylic acid cycle (TCA) intermediates. This approach was evaluated in rat brain using malonate-perfusion (10–50 mM) and endothelin-1 (ET-1)-induced transient cerebral ischemia. In the malonate model, the expected changes upon inhibition of succinate dehydrogenase (SDH) were observed, i.e., an increase in endogenous succinate and decreases in fumaric acid and malic acid. The inhibition was further elaborated by incorporation of 13C into specific TCA intermediates from 13C-labeled succinate. In the ET-1 model, increases in non-labeled TCA metabolites (reflecting release of intracellular compounds) and decreases in 13C-labeled TCA metabolites (reflecting inhibition of de novo synthesis) were observed. The analysis of 13C incorporation provides further layers of information to identify metabolic disturbances in experimental models and neuro-intensive care patients.

Tricarboxylic acid cycle activity in perfused rat lungs after O2 exposure

1992 ◽  
Vol 262 (4) ◽  
pp. L495-L501 ◽  
Author(s):  
D. J. Bassett ◽  
S. S. Reichenbaugh
Keyword(s):  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Enzyme Inactivation ◽  
Pyridine Nucleotides ◽  
Acid Cycle ◽  
Metabolic Conditions ◽  
Steady State Levels ◽  
14Co2 Production ◽  
Tricarboxylic Acid Cycle Intermediates

O2-induced impairment of mitochondrial energy generation was examined in intact lungs isolated from rats after 18-30 h exposure to either air or 100% O2 in vivo. Mitochondrial metabolic rates were determined by separate measurements of 14CO2 production from [1-14C]pyruvate and [U-14C]palmitate, perfused under normal and stimulated metabolic conditions brought about by perfusion with the uncoupler of oxidative phosphorylation, 2,4-dinitrophenol (DNP). In the absence of DNP, O2 exposure did not significantly alter 14CO2 productions from either substrate. DNP increased lung pyruvate and palmitate catabolism to CO2 twofold in air-exposed lungs but did not alter 14CO2 production in lungs isolated from O2-exposed rats. These data demonstrated an O2-induced impairment of maximal mitochondrial metabolism of both pyruvate and palmitate that could not be explained by alterations in tissue free coenzyme A or by loss of pyridine nucleotides. However, comparisons of the steady-state levels of tricarboxylic acid cycle intermediates between O2- and air-exposed lungs did identify isocitrate dehydrogenase as a possible site of O2-induced enzyme inactivation.

Cyclometalated iridium(iii) complexes induce mitochondria-derived paraptotic cell death and inhibit tumor growthin vivo

2018 ◽  
Vol 47 (20) ◽  
pp. 6942-6953 ◽  
Author(s):  
Liang He ◽  
Kang-Nan Wang ◽  
Yue Zheng ◽  
Jian-Jun Cao ◽  
Ming-Fang Zhang ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Growth ◽  
Mitochondrial Dysfunction

A potent anticancer Ir(iii) complex induces paraptotic cell death by causing mitochondrial dysfunction rapidly and inhibits tumor growth significantlyin vivo.

scholarly journals Control of phosphoenolpyruvate synthesis in guinea-pig mitochondria

1973 ◽  
Vol 132 (3) ◽  
pp. 553-557 ◽  
Author(s):  
M. B. Wilson
Keyword(s):  
Guinea Pig ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
O2 Consumption ◽  
Acid Cycle ◽  
Tricarboxylic Acid Cycle Intermediates

1. The synthesis of phosphoenolpyruvate and the O2 consumption from the tricarboxylic acid-cycle intermediates citrate, α-oxoglutarate, malate and succinate by guinea-pig mitochondria were compared. Malate was the most effective of these precursors; there was no synthesis of phosphoenolpyruvate from succinate. 2. The addition of palmitate, acetoacetate and ATP enhanced the synthesis of phosphoenolpyruvate from citrate and α-oxoglutarate. Palmitate and ATP increased the O2 consumption, whereas acetoacetate had no effect on this parameter. 3. Octanoate depressed the synthesis of phosphoenolpyruvate from citrate, α-oxoglutarate and malate and increased the O2 consumption. Pentenoic acid had no effect on phosphoenolpyruvate synthesis from any of the substrates used, although it increased the uptake of O2. These findings might be relevant to the control of gluconeogenesis in vivo.

scholarly journals Haploinsufficiency due to a novel ACO2 deletion causes mitochondrial dysfunction in fibroblasts from a patient with dominant optic nerve atrophy

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Marie Anne-Catherine Neumann ◽  
Dajana Grossmann ◽  
Simone Schimpf-Linzenbold ◽  
Dana Dayan ◽  
Katarina Stingl ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Optic Nerve ◽  
Mitochondrial Dysfunction ◽  
Tricarboxylic Acid Cycle ◽  
Cerebellar Atrophy ◽  
Cortical Atrophy ◽  
Mitochondrial Morphology ◽  
Optic Nerve Atrophy ◽  
Mtdna Mutations

Abstract ACO2 is a mitochondrial protein, which is critically involved in the function of the tricarboxylic acid cycle (TCA), the maintenance of iron homeostasis, oxidative stress defense and the integrity of mitochondrial DNA (mtDNA). Mutations in the ACO2 gene were identified in patients suffering from a broad range of symptoms, including optic nerve atrophy, cortical atrophy, cerebellar atrophy, hypotonia, seizures and intellectual disabilities. In the present study, we identified a heterozygous 51 bp deletion (c.1699_1749del51) in ACO2 in a family with autosomal dominant inherited isolated optic atrophy. A complementation assay using aco1-deficient yeast revealed a growth defect for the mutant ACO2 variant substantiating a pathogenic effect of the deletion. We used patient-derived fibroblasts to characterize cellular phenotypes and found a decrease of ACO2 protein levels, while ACO2 enzyme activity was not affected compared to two age- and gender-matched control lines. Several parameters of mitochondrial function, including mitochondrial morphology, mitochondrial membrane potential or mitochondrial superoxide production, were not changed under baseline conditions. However, basal respiration, maximal respiration, and spare respiratory capacity were reduced in mutant cells. Furthermore, we observed a reduction of mtDNA copy number and reduced mtDNA transcription levels in ACO2-mutant fibroblasts. Inducing oxidative stress led to an increased susceptibility for cell death in ACO2-mutant fibroblasts compared to controls. Our study reveals that a monoallelic mutation in ACO2 is sufficient to promote mitochondrial dysfunction and increased vulnerability to oxidative stress as main drivers of cell death related to optic nerve atrophy.

scholarly journals A Biostimulant Obtained from the Seaweed Ascophyllum nodosum Protects Arabidopsis thaliana from Severe Oxidative Stress

2020 ◽  
Vol 21 (2) ◽  
pp. 474 ◽  
Author(s):  
Mohammad Amin Omidbakhshfard ◽  
Neerakkal Sujeeth ◽  
Saurabh Gupta ◽  
Nooshin Omranian ◽  
Kieran J. Guinan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Arabidopsis Thaliana ◽  
Cell Death ◽  
Foliar Application ◽  
Tricarboxylic Acid Cycle ◽  
Ascophyllum Nodosum ◽  
Marker Genes ◽  
Lipidome Analysis ◽  
Tricarboxylic Acid Cycle Intermediates ◽  
Carbohydrate Metabolism Genes

Abiotic stresses cause oxidative damage in plants. Here, we demonstrate that foliar application of an extract from the seaweed Ascophyllum nodosum, SuperFifty (SF), largely prevents paraquat (PQ)-induced oxidative stress in Arabidopsis thaliana. While PQ-stressed plants develop necrotic lesions, plants pre-treated with SF (i.e., primed plants) were unaffected by PQ. Transcriptome analysis revealed induction of reactive oxygen species (ROS) marker genes, genes involved in ROS-induced programmed cell death, and autophagy-related genes after PQ treatment. These changes did not occur in PQ-stressed plants primed with SF. In contrast, upregulation of several carbohydrate metabolism genes, growth, and hormone signaling as well as antioxidant-related genes were specific to SF-primed plants. Metabolomic analyses revealed accumulation of the stress-protective metabolite maltose and the tricarboxylic acid cycle intermediates fumarate and malate in SF-primed plants. Lipidome analysis indicated that those lipids associated with oxidative stress-induced cell death and chloroplast degradation, such as triacylglycerols (TAGs), declined upon SF priming. Our study demonstrated that SF confers tolerance to PQ-induced oxidative stress in A. thaliana, an effect achieved by modulating a range of processes at the transcriptomic, metabolic, and lipid levels.

scholarly journals Loss of mitochondrial transcription factor A in neural stem cells leads to immature brain development and triggers the activation of the integral stress response in vivo

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0255355
Author(s):  
Rintaro Kuroda ◽  
Kaoru Tominaga ◽  
Katsumi Kasashima ◽  
Kenji Kuroiwa ◽  
Eiji Sakashita ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Transcription Factor ◽  
Stress Response ◽  
Neural Stem Cells ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Transcription ◽  
Mitochondrial Transcription Factor ◽  
Mitochondrial Transcription Factor A

Mitochondrial dysfunction is significantly associated with neurological deficits and age-related neurological diseases. While mitochondria are dynamically regulated and properly maintained during neurogenesis, the manner in which mitochondrial activities are controlled and contribute to these processes is not fully understood. Mitochondrial transcription factor A (TFAM) contributes to mitochondrial function by maintaining mitochondrial DNA (mtDNA). To clarify how mitochondrial dysfunction affects neurogenesis, we induced mitochondrial dysfunction specifically in murine neural stem cells (NSCs) by inactivating Tfam. Tfam inactivation in NSCs resulted in mitochondrial dysfunction by reducing respiratory chain activities and causing a severe deficit in neural differentiation and maturation both in vivo and in vitro. Brain tissue from Tfam-deficient mice exhibited neuronal cell death primarily at layer V and microglia were activated prior to cell death. Cultured Tfam-deficient NSCs showed a reduction in reactive oxygen species produced by the mitochondria. Tfam inactivation during neurogenesis resulted in the accumulation of ATF4 and activation of target gene expression. Therefore, we propose that the integrated stress response (ISR) induced by mitochondrial dysfunction in neurogenesis is activated to protect the progression of neurodegenerative diseases.

scholarly journals Toxic Markers of Matrine Determined Using1H-NMR-Based Metabolomics in Cultured CellsIn Vitroand RatsIn Vivo

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Zhonghuang Li ◽  
Liang Zheng ◽  
Jian Shi ◽  
Guiyu Zhang ◽  
Linlin Lu ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Skin Diseases ◽  
Tricarboxylic Acid Cycle ◽  
High Dose ◽  
Toxicological Effects ◽  
Toxicity Biomarkers ◽  
Tricarboxylic Acid Cycle Intermediates ◽  
Dose Dependent

Matrine is one of the main bioactive alkaloids ofSophora flavescensAiton, which has been widely used to treat various diseases in China. These diseases include viral hepatitis, liver fibrosis, cardiac arrhythmia, skin diseases, and tumors. However, matrine is also the main toxic compound of this herb, and the available biomarkers are not reliable in detecting or quantifying matrine risk. Metabolomics is a powerful tool used to identify early toxicity biomarkers that are specific indicators of damage to biosystems. This study aimed to find the potential biomarkers of the matrine-induced toxic effects in rats and HepG2 cells. The toxicological effects of rats induced by matrine could be derived from the elevated taurine and trimethylamine N-oxide levels and the depletion in hippurate and tricarboxylic acid cycle intermediates, such as 2-oxoglutarate, citrate, and succinate in the urine. Cell metabolomics revealed that the levels of alanine, choline, glutathione, lactate, phosphocholine, and cholesterol showed dose-dependent decreases, whereas the levels of taurine, fatty acid, and unsaturated fatty acid showed dose-dependent increases. Overall, a significant perturbation of metabolites in response to high dose of matrine was observed bothin vivoandin vitro, and the selected metabolites particularly represent an attractive marker for matrine-induced toxicity.

scholarly journals TRAP1 Provides Protection Against Myocardial Ischemia-Reperfusion Injury by Ameliorating Mitochondrial Dysfunction

2015 ◽  
Vol 36 (5) ◽  
pp. 2072-2082 ◽  
Author(s):  
Peng Zhang ◽  
Yong Lu ◽  
Dong Yu ◽  
Dadong Zhang ◽  
Wei Hu
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ros Generation ◽  
Complex Activity ◽  
Atp Production

Background: Tumor necrosis factor receptor-associated protein 1 (TRAP1), an essential mitochondrial chaperone is induced in rat hearts following ischemia/reperfusion (I/R), but its role in myocardial I/R injury is unclear. The present study examined the function of TRAP1 in cardiomyocyte hypoxia/reoxygenation injury in vitro and myocardial I/R injury in vivo. Methods: HL-1 cardiomyocytes transfected with TRAP1 or vector were subjected to simulated I/R (SI/R) in vitro. Cell death and mitochondrial function were assessed. Wild type (WT) and TRAP1 knockout (TRAP1 KO) mice were subjected to cardiac I/R in vivo. The infarct size and myocardial apoptosis were determined. WT and TRAP1 KO cardiomyocytes were subjected to SI/R in vitro. Mitochondrial function was assessed. Results: TRAP1 overexpression protects HL-1 cardiomyocytes from SI/R-induced cell death in vitro. The reduced cell death was associated with decreased ROS generation, better-preserved mitochondrial ETC complex activity, membrane potential, and ATP production, as well as delayed mPTP opening. Loss of TRAP1 aggravates SI/R-induced mitochondrial damage in cardiomyocytes in vitro and myocardial I/R injury and apoptosis in vivo. Conclusion: The results of the present study show that TRAP1 provides cardioprotection against myocardial I/R by ameliorating mitochondrial dysfunction.

Sign in / Sign up

Export Citation Format

Share Document