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Karavyraki 2022 MitoFit + ([[Porter 2022 Abstract Bioblast]]: In an e … [[Porter 2022 Abstract Bioblast]]: In an endeavour to understand the metabolic phenotype behind oral squamous cell carcinomas, we characterised the bioenergetic profile of a human tongue derived cancer cell line (SCC-4 cells) and compared this profile to a pre-cancerous dysplastic oral keratinocyte (DOK) cell line also derived from human tongue. The human SCC-4 cancer cells had greater mitochondrial densitydensity but lower mitochondrial O2 flow per cell than DOK cells. The lower oxygen consumption rate in SCC-4 cells can be partially explained by lower NADH-related enzymatic activity and lower mitochondrial Complex I activity when compared to pre-cancerous DOK cells. In addition, SCC-4 cells have greater extracellular acidification rate (an index of glycolytic flux) when compared to DOK cells. In addition, treatment with recombinant human IL-6 (rhIL-6), known to drive anoikis resistance in SCC-4 cells but not DOK cells, impairs oxygen consumption in SCC-4 but not DOK cells, without affecting mitochondrial density. We conclude that SCC-4 cells have a less oxidative phenotype compared to DOK cells and that IL-6 attenuates mitochondrial function in SCC-4 cells while increasing glycolytic flux.-4 cells while increasing glycolytic flux.)
Abed Rabbo 2022 MitoFit + ([[Stiban 2022 Abstract Bioblast]]: Mitocho … [[Stiban 2022 Abstract Bioblast]]: Mitochondrial ailments are diverse and devastating. Defects in mitochondrial DNA or its products lead to wide range of deficiencies in the mitochondrial electron transfer system and its ensuing energy production. Accessory proteins required for the assembly and function of the respiratory complexes are also required for healthy, coupled, and energy-producing mitochondria. Recently, the protein nucleotide binding protein like (NUBPL or IND1) was identified as an iron-sulfur cluster transfer protein specifically for Complex I. Since the presence of multiple iron-sulfur clusters in Complex I is necessary for its activity, deficiency in NUBPL leads to severely dysfunctional mitochondria, with upregulated compensatory Complex II activity. Here we present a short review of the debilitating disease related to NUBPL deficiency.ating disease related to NUBPL deficiency.)
Torres-Quesada 2022 MitoFit Kinase + ([[Torres-Quesada 2022 Abstract Bioblast]]: … [[Torres-Quesada 2022 Abstract Bioblast]]: Protein kinases take the center stage in numerous signaling pathways by phosphorylating compartmentalized protein substrates for controlling cell proliferation, cell cycle and metabolism. Kinase dysfunctions have been linked to numerous human diseases such as cancer. This has led to the development of kinase inhibitors which aim to target oncogenic kinase activities. The specificity of the cancer blockers depends on the range of targeted kinases. Therefore, the question arises of how cell-type-specific off-target effects impair the specificities of cancer drugs. Blockade of kinase activities has been shown to converge on the energetic organelle, the mitochondria. In this review, we highlight examples of selected major kinases which impact mitochondrial signaling. Further, we discuss pharmacological strategies to target kinase activities which are linked to cancer progression and redirecting mitochondrial function. Finally, we propose that cell-based recordings of mitochondrial bioenergetic states might predict off-target or identify specific on-target effects of kinase inhibitors.ic on-target effects of kinase inhibitors.)
Heichler 2022 MitoFit + ([[Wolf 2022 Abstract Bioblast]]: The CYRIS … [[Wolf 2022 Abstract Bioblast]]: The CYRIS® analysis platform is a multi-sensory approach to extract a large amount of information from a single cell-based assay automatically and in real-time. To demonstrate its capabilities, we performed an in-vitro hepatotoxicity assay with Acetaminophen and HepG2, with simultaneous monitoring of the key parameters oxygen consumption rate (OCR), extracellular acidification rate (ECAR), impedance and microscopic imaging. After 12 hours prior treatment measurement, different concentrations of Acetaminophen were tested over 24 hours, followed by 12 hours washout. The metabolic results showed a strong time- and dose-dependent change of OCR and ECAR through Acetaminophen. Morphologic changes monitored by impedance and microscopic imaging underpin these metabolic effects. The washout of Acetaminophen results in cellular regeneration in all parameters up to a concentration of 10 mM. The continuous measurement of OCR, ECAR, impedance and microscopic imaging enables multiparametric monitoring of cellular metabolic responses due to Acetaminophen in a single assay and provides an overall picture of its hepatotoxic effects.verall picture of its hepatotoxic effects.)
PSSA 2016 Cape Town ZA + ([http://physiolsoc.org.za/pssa-2016-conference/ PSSA conference 2016])
SSMFRP - Redox Medicine + ([http://ssmfrp.edu.rs/home SSMFRP - Redox … [http://ssmfrp.edu.rs/home SSMFRP - Redox Medicine] - 2015 Sep 25-26, Belgrade, RS'''The motto of this congress is Redox medicine, with the aim to unite research related to mitochondria and redox processes in pathophysiological conditions.''' :» [[Media: SSMFRP Preliminary scientific program.pdf| Preliminary scientific program]][Media: SSMFRP Preliminary scientific program.pdf| Preliminary scientific program]])
Laner 2013 ASMRM + ([http://www.asmrm2013.com/common_files/pro … [http://www.asmrm2013.com/common_files/program.asp Luncheon Seminar Nov 5, 12:10-12:50, ASMRM2013, Seoul, South Korea] - [http://www.oroboros.at/?O2k-workshops IOC81][[High-resolution respirometry]] (HRR) has become established world-wide for the diagnosis of mitochondrial respiratory control and OXPHOS analysis, reflected in [[O2k-Publications|>1,000 O2k-publications]] using the Oroboros Oxygraph-2k. The [[O2k-Fluorescence LED2-Module]] is a recent extension of the Oxygraph-2k for combining HRR and fluorometric measurements. Two major applications of O2k-Fluorometry are presented. # [[MiPNet18.05 Amplex-Mouse-heart|H2O2 production measured with Amplex® Ultrared in mouse heart mitochondria]] was not only a function of respiratory substrate and coupling state, but depended strongly on experimental oxygen levels below and even above air saturation of the respiration medium.# Mitochondrial membrane potential was measured with [[Safranin]] (2 µM) with high sensitivity particularly in the range of low membrane potentials. However, Safranin specifically inhibited Complex I linked respiration and the phosphorylation system, such that meaningful applications had to be restricted to Complex II linked respiration with succinate and rotenone. Inhibitory side effects must be critically evaluated for any probe of mitochondrial membrane potential. These examples illustrate the sensitivity and wide range of applicability of O2k-fluorometry and demonstrate the importance of combining measurements of hydrogen peroxide production and mitochondrial membrane potential with simultaneous monitoring of oxygen concentration and oxygen consumption.multaneous monitoring of oxygen concentration and oxygen consumption.)
Stem Cell Energetics 2014 + ([http://www.cell-symposia-stem-cell-energetics.com/ Cell Symposium Stem Cell Energetics 2014], Berkeley, CA, US.)
ISMM2014 + ([http://www.ismm2014.org/Pages/default.aspx '''World Congress on High Altitude Medicine and Physiology'''], ISMM, Bolzano, Italy; including '''[[MiPNet19.05 | 90th Oroboros O2k-Workshop]]'''.)
EUROMIT2017 Cologne DE + ([https://euromit2017.org/ EUROMIT2017] International Meeting on Mitochondrial Pathology, Cologne, DE)
Analytica China 2024 Shanghai CN + (analytica China, Shanghai, China, 2024)
Cecatto 2020 Toxicol In Vitro + (cis-5-Tetradecenoic (cis-5) and myristic ( … cis-5-Tetradecenoic (cis-5) and myristic (Myr) acids predominantly accumulate in patients affected by very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. They commonly manifest myopathy with muscular pain and rhabdomyolysis, whose underlying mechanisms are poorly known. Thus, in the present study we investigated the effects of cis-5 and Myr on mitochondrial bioenergetics and Ca2+ homeostasis in rat skeletal muscle. cis-5 and Myr decreased ADP-stimulated (state 3) and CCCP-stimulated (uncoupled) respiration, especially when mitochondria were supported by NADH-linked as compared to FADH2-linked substrates. In contrast, these fatty acids increased resting respiration (state 4). Similar effects were observed in skeletal muscle fibers therefore validating the data obtained with isolated mitochondria. Furthermore, cis-5 and Myr markedly decreased mitochondrial membrane potential and Ca2+ retention capacity that were avoided by cyclosporin A plus ADP and ruthenium red, indicating that cis-5 and Myr induce mitochondrial permeability transition (MPT). Finally, docosanoic acid did not disturb mitochondrial homeostasis, indicating selective effects for Myr and cis-5. Taken together, our findings indicate that major long-chain fatty acids accumulating in VLCAD deficiency behave as metabolic inhibitors, uncouplers of oxidative phosphorylation and MPT inducers. It is presumed that these pathomechanisms contribute to the muscular symptoms and rhabdomyolysis observed in patients affected by VLCAD deficiency.Copyright © 2019 Elsevier Ltd. All rights reserved.eficiency. Copyright © 2019 Elsevier Ltd. All rights reserved.)
EPN Autumn School Series Ebsdorfergrund DE + (he European Psychoneuroimmunology Autumn S … he European Psychoneuroimmunology Autumn School Series - the skin-brain axis and the breaking of barriers, Ebsdorfergrund, Germany, 2023 == Venue == :::: Schloss Rauischholzhausen:::: Ferdinand-von-Stumm-Straße:::: 35085 Ebsdorfergrund, Germany::::[https://www.uni-giessen.de/en/about/rhh Location]== Program ==:::: Please find the preliminary program [https://www.uni-giessen.de/de/fbz/fb10/institute_klinikum/institute/vphysbio/forschung/congresses/EPN%20Autumn%20School%20Series/Preliminary%20programs '''»here''']== Organizers == :::: The school is organized by the [https://pnieurope.eu/ European PNI Network (EPN)] and [https://www.gebin.org/ German-Endocrine-Brain-Immune-Network (GEBIN)]:::: Eva MJ Peters:::: Christoph Rummel:::: Karsten Krüger:::: Adriana del Reyl :::: Karsten Krüger :::: Adriana del Rey)
Komlodi 2021 MitoFit Q + (https://www.bioenergetics-communications.o … https://www.bioenergetics-communications.org/index.php/bec/article/view/komlodi_2021_amr''Published in'' [[Bioenergetics Communications]]: 2021-11-11::: Komlódi T, Cardoso LHD, Doerrier C, Moore AL, Rich PR, Gnaiger E (2021) Coupling and pathway control of coenzyme Q redox state and respiration in isolated mitochondria. Bioenerg Commun 2021.3. https://doi.org/10.26124/bec:2021-0003::: Version 4 ('''v4''') 2021-09-15 [http://www.mitofit.org//images/9/91/Komlodi_2021_MitoFit_Q.pdf doi:10.26124/mitofit:2021-0002.v4] ::: Version 3 (v3) 2021-09-01 [https://www.mitofit.org/images/archive/9/91/20210915113223%21Komlodi_2021_MitoFit_Q.pdf doi:10.26124/mitofit:2021-0002.v3]::: Version 2 (v2) 2021-05-06 [https://wiki.oroboros.at/images/archive/9/91/20210901145411%21Komlodi_2021_MitoFit_Q.pdf doi:10.26124/mitofit:2021-0002.v2]::: Version 1 (v1) 2021-02-18 [https://wiki.oroboros.at/images/archive/9/91/20210505231707%21Komlodi_2021_MitoFit_Q.pdf doi:10.26124/mitofit:2021-0002] - [http://www.mitofit.org/index.php/File:Komlodi_2021_MitoFit_Q.pdf#Links_to_all_versions »Link to all versions«] Redox states of the mitochondrial coenzyme Q pool, which reacts with the electron transfer system, reflect the balance between (''1'') reducing capacities of electron flow from fuel substrates converging at the Q-junction, (''2'') oxidative capacities downstream of Q to O2, and (''3'') the load on the OXPHOS system utilizing or dissipating the protonmotive force. A three-electrode sensor (Rich 1988; Moore et al 1988) was implemented into the NextGen-O2k to monitor continuously the redox state of CoQ2 added as a Q-mimetic simultaneously with O2 consumption. The Q-Module was optimized for high signal-to-noise ratio, minimum drift, and minimum oxygen diffusion. CoQ2 equilibrates in the same manner as Q at Complexes CI, CII and CIII. The CoQ2 redox state is monitored amperometrically with the working electrode, which is poised at CoQ2 redox peak potentials determined by cyclic voltammetry. The voltammogram also provides quality control of the Q-sensor and reveals chemical interferences. The CoQ2 redox state and O2 consumption were measured simultaneously in isolated mouse cardiac and brain mitochondria. CoQ2 ― and by implication mitochondrial Q ― was more oxidized when O2 flux was stimulated by coupling control: when energy demand increased from LEAK to OXPHOS and electron transfer capacities in the succinate pathway. In contrast, CoQ2 was more reduced when O2 flux was stimulated by pathway-control of electron input capacities, increasing from the NADH (N)- to succinate (S)-linked pathway which converge at the Q-junction, with CI-Q-CIII and CII-Q-CIII segments, respectively. N- and S- respiratory pathway capacities were not completely additive, compatible with partitioning of Q intermediary between the solid-state and liquid-state models of supercomplex organization. The direct proportionality of CoQ2 reduction and electron input capacities through the CI-Q-CIII and CII-Q-CIII segments suggests that CoQ2 is accurately mimicking mitochondrial Q-redox changes. and electron input capacities through the CI-Q-CIII and CII-Q-CIII segments suggests that CoQ2 is accurately mimicking mitochondrial Q-redox changes.)
Kelly 2015 Biotechnol J + (microRNA engineering of CHO cells has alre … microRNA engineering of CHO cells has already proved successful in enhancing various industrially relevant phenotypes and producing various recombinant products. A single miRNA's ability to interact with multiple mRNA targets allows their regulatory capacity to extend to processes such as cellular metabolism. Various metabolic states have previously been associated with particular CHO cell phenotypes such as glycolytic or oxidative metabolism accommodating growth and productivity, respectively. miR-23 has previously been demonstrated to play a role in glutamate metabolism resulting in enhanced oxidative phosphorylation through the TCA cycle. Re-programming cellular bioenergetics through miR-23 could tip the balance, forcing mammalian production cells to be more productive by favoring metabolic channelling into oxidative metabolism. CHO clones depleted of miR-23 using a miR-sponge decoy demonstrated an average ∼three-fold enhanced specific productivity with no impact on cell growth. Using a cell respirometer, mitochondrial activity was found to be enhanced by ∼30% at Complex I and II of the electron transport system. Additionally, label-free proteomic analysis uncovered various potential novel targets of miR-23 including LE™1 and IDH1, both implicated in oxidative metabolism and mitochondrial activity. These results demonstrate miRNA-based engineering as a route to re-programming cellular metabolism resulting in increased productivity, without affecting growth.ed productivity, without affecting growth.)
Mitochondrial Medicine 2019 Zurich CH + (mitoNET Meeting and Mitochondrial Medicine congress (Germany, Austria, Switzerland), Zurich, Switzerland, 2019)
MtFOIE GRAS Mid-term meeting Pisa IT + (mtFOIE GRAS Mid-term meeting, Pisa, Italy, 2018)
McKeehan 1982 Cell Biol Int Rep + (mtNAD-ME is crucial for the metabolism generating pyruvate from glutamine, which is the most abundant single amino acid in plasma, tissues and cell culture media. 'Glutaminolysis' is analogous to the glycolysis pathway that converts glucose to pyruvate.)
Wu 2022 Front Chem + (nFe3O4 was prepared from waste iron slag a … nFe3O4 was prepared from waste iron slag and loaded onto air stone (named magnetic air stone or MAS in the following text). The main component of air stone is carborundum. To study the magnetic effects of MAS on denitrification, a biofilm reactor was built, and its microbial community structure and electron transfer in denitrification were analyzed. The results showed that MAS improved the performance of the reactor in both carbon and nitrogen removal compared with air stone (AS) control, and the average removal efficiencies of COD, TN, and NH4 +-N increased by 17.15, 16.1, and 11.58%, respectively. High-throughput sequencing revealed that magnetism of MAS had a significant effect on the diversity and richness of microorganisms in the biofilm. The MAS also reduced the inhibition of rotenone, mipalene dihydrochloride (QDH), and sodium azide on the respiratory chain in denitrification and enhanced the accumulation of nitrite, in order to provide sufficient substrate for the following denitrification process. Therefore, the denitrification process is accelerated by the MAS. The results allowed us to deduce the acceleration sites of MAS in the denitrification electron transport chain. The existence of MAS provides a new rapid method for the denitrifying electron transport process. Even in the presence of respiratory inhibitors of denitrifying enzymes, the electron transfer acceleration provided by MAS still exists objectively. This is the mechanism through which MAS can restore the denitrification process inhibited by respiratory inhibitors to a certain extent.espiratory inhibitors to a certain extent.)
Jansen-Duerr 2016 Abstract Mito Xmas Meeting Innsbruck + (no abstract)

14th Mitochondrial Disease Conference 2024 Padova IT + (tba)

AMCTB 2016 Anal Methods + (z-Scores were devised to provide a transpa … z-Scores were devised to provide a transparent but widely-applicable scoring system for participants in proficiency tests for analytical laboratories. The essential idea is to provide an appropriate scaling of the difference between a participant’s result and the ‘assigned value’ for the concentration of the analyte. Interpretation of a z-score is straightforward but some aspects need careful attention to avoid misconception. Over time several related scores have been devised to cope with a diversified range of applications. The main types of score have recently been codified in ISO 13528 (2015).ecently been codified in ISO 13528 (2015).)
Laner 2013 Mitochondr Physiol Network MiP2013 + (» [[MiP2013 Abstracts]] » [[Laner 2013 Mitochondr Physiol Network MiP2013]])
Lehto 2022 Neurochem Res + (ß-Hydroxybutyrate (BHB) is a ketone body f … ß-Hydroxybutyrate (BHB) is a ketone body formed in high amounts during lipolysis and fasting. Ketone bodies and the ketogenic diet were suggested as neuroprotective agents in neurodegenerative disease. In the present work, we induced transient ischemia in mouse brain by unilaterally occluding the middle cerebral artery for 90 min. BHB (30 mg/kg), given immediately after reperfusion, significantly improved the neurological score determined after 24 h. In isolated mitochondria from mouse brain, oxygen consumption by the complexes I, II and IV was reduced immediately after ischemia but recovered slowly over 1 week. The single acute BHB administration after reperfusion improved complex I and II activity after 24 h while no significant effects were seen at later time points. After 24 h, plasma and brain BHB concentrations were strongly increased while mitochondrial intermediates (citrate, succinate) were unchanged in brain tissue. Our data suggest that a single administration of BHB may improve mitochondrial respiration for 1-2 days but not for later time points. Endogenous BHB formation seems to complement the effects of exogenous BHB administration.e effects of exogenous BHB administration.)
Fets 2018 Nat Chem Biol + (α-Ketoglutarate (αKG) is a key node in man … α-Ketoglutarate (αKG) is a key node in many important metabolic pathways. The αKG analog N-oxalylglycine (NOG) and its cell-permeable prodrug dimethyloxalylglycine (DMOG) are extensively used to inhibit αKG-dependent dioxygenases. However, whether NOG interference with other αKG-dependent processes contributes to its mode of action remains poorly understood. Here we show that, in aqueous solutions, DMOG is rapidly hydrolyzed, yielding methyloxalylglycine (MOG). MOG elicits cytotoxicity in a manner that depends on its transport by monocarboxylate transporter 2 (MCT2) and is associated with decreased glutamine-derived tricarboxylic acid-cycle flux, suppressed mitochondrial respiration and decreased ATP production. MCT2-facilitated entry of MOG into cells leads to sufficiently high concentrations of NOG to inhibit multiple enzymes in glutamine metabolism, including glutamate dehydrogenase. These findings reveal that MCT2 dictates the mode of action of NOG by determining its intracellular concentration and have important implications for the use of (D)MOG in studying αKG-dependent signaling and metabolism.ng αKG-dependent signaling and metabolism.)
Bir 2013 Abstract MiP2013 + (α-Synucleinopathy and mitochondrial dysfun … α-Synucleinopathy and mitochondrial dysfunction are important elements of sporadic Parkinson’s disease (PD) pathogenesis [1]. It is, however, not clear whether the accumulated α-synuclein in degenerating dopaminergic neurons in PD causes mitochondrial injury and subsequent cell death. Our earlier study has shown that α-synuclein causes functional impairment of rat brain mitochondria incubated in vitro [2].Mitochondrial membrane potential was measured using the carbocyanine dye JC1, and the phosphorylation capacity determined spectrophotometrically from inorganic phosphate utilization [2,3]. The respiratory functions of mitochondria in isolated preparations and within intact cells were analyzed by high-resolution respirometry. α-Synuclein accumulation within SHSY5Y cells was induced by lactacystin treatment and detected by immunoblotting. The transfection of SHSY5Y cells with α synuclein specific SiRNA was carried out using the lipofectamine kit (Invitrogen).Our results show that α-synuclein causes a loss of membrane potential and phosphorylation capacity with alterations in respiratory parameters in isolated rat brain mitochondria. Some of these effects were inhibited very significantly by cyclosporine (1 μM). When SHSY5Y cells were exposed to 5 μM lactacystin for 24 h, α-synuclein accumulation occured intracellularly as detected by immunoblotting experiments. Further, lactacystin treatment of SHSY5Y cells also leads to mitochondrial dysfunction and cell death concomitant with α synuclein accumulation. To confirm the involvement of α synuclein in lactacystin induced mitochondrial dysfunction, the effects of cyclosporine and the gene silencing of α-synuclein with specific SiRNA on these phenomena are being investigated.on these phenomena are being investigated.)
Sobotka 2014 Abstract IOC95 + (α-Tocopheryl succinate (TOS) is a redox-si … α-Tocopheryl succinate (TOS) is a redox-silent analogue of vitamin E with specific anti-tumorous effects. According to some studies, TOS suppresses cell growth and induces apoptosis in cancer cells [1-3]. The inhibitory effect on transformed cells is related to an increase in reactive oxygen species (ROS) production possibly via inhibition of respiratory complex II - specifically mitochondrial flavoprotein-dependent enzymes succinate dehydrogenase (SDH) and glycerol-3-phosphate dehydrogenase (mGPDH) [1-4]. On the molecular level the effect of TOS is explained by interaction of TOS with the proximal and distal CoQ-binding sites of complex II [4]. However such effect was not found in non-cancer cells [1, 3].The aim of our study was to assess the inhibitory action of TOS on complex II in rat heart and liver homogenate and mitochondria. The maximum respiratory capacity of complex II induced by addition of succinate, cytochrome c and ADP was measured using the high resolution respirometry (HRR) Oroboros 2K. We evaluated the TOS inhibitory action on complex II respiration during concentration increase. The strong inhibitory effect of TOS on complex II respiration was found at the concentration range between 150-500 μM. Our results showed that both liver and heart mitochondria were more sensitive to TOS inhibitory action in comparison to homogenate.Our study using HRR method showed a TOS inhibitory action on complex II activity. Strong inhibitory effect was detected on heart and liver mitochondria as well as on the homogenate. Lower sensitivity of liver homogenate compared to mitochondria may be the result of the presence of cytosolic esterases which split the molecule of TOS to α-tocopherol and succinate [3] or due to binding of TOS to cytosolic membrane structures.References:1. Angulo-Molina, A., et al., The Role of Alpha Tocopheryl Succinate (alpha-TOS) as a Potential Anticancer Agent. Nutr Cancer, 2013.2. Zhao, Y., J. Neuzil, and K. Wu, Vitamin E analogues as mitochondria-targeting compounds: from the bench to the bedside? Mol Nutr Food Res, 2009. 53(1): p. 129-39.3. Neuzil, J., et al., Molecular mechanism of 'mitocan'-induced apoptosis in cancer cells epitomizes the multiple roles of reactive oxygen species and Bcl-2 family proteins. FEBS Lett, 2006. 580(22): p. 5125-9.4. Rauchova, H., M. Vokurkova, and Z. Drahota, Inhibition of mitochondrial glycerol-3-phosphate dehydrogenase by alpha-tocopheryl succinate. Int J Biochem Cell Biol, 2014. 53: p. 409-13. J Biochem Cell Biol, 2014. 53: p. 409-13.)
Rauchova 2014 Int J Biochem Cell Biol + (α-Tocopheryl succinate (TOS), a redox-sile … α-Tocopheryl succinate (TOS), a redox-silent analogue of vitamin E, suppresses cell growth in a numberof clinical and experimental cancers, inhibits mitochondrial succinate dehydrogenase (SDH) and activatesreactive oxygen species (ROS) generation. The aim of this study was to test whether TOS alsoinhibits glycerol-3-phosphate dehydrogenase (mGPDH), another flavoprotein-dependent enzyme of themitochondrial respiratory chain because there are differences between electron transfer pathway fromSDH and mGPDH to coenzyme Q pool. For our experiments brown adipose tissue mitochondria withhigh expression of mGPDH were used. Our data showed that inhibition of glycerol-3-phosphate (GP)-dependent oxygen consumption by TOS was more pronounced than the succinate (SUC)-dependent one(50% inhibition was reached at 10 μmol/l TOS vs. 80 μmol/l TOS, respectively). A comparison of theinhibitory effect of TOS on GP-oxidase, GP-cytochrome c oxidoreductase and GP-dehydrogenase activitiesshowed that TOS directly interacts with the dehydrogenase. After TOS application the GP-dependentgeneration of ROS was highly depressed. It may thus be concluded that TOS-induced inhibition of mGPDHis more pronounced than TOS-induced inhibition of SDH and that the inhibitory effect of TOS for bothsubstrates is exerted at different locations of the particular dehydrogenases. Our data indicate that theinhibition of mGPDH activity could also play a role in TOS-induced growth suppression in neoplastic cells.ed growth suppression in neoplastic cells.)
Fets 2022 Commun Biol + (α-ketoglutarate (αKG) is a central metabol … α-ketoglutarate (αKG) is a central metabolic node with a broad influence on cellular physiology. The αKG analogue N-oxalylglycine (NOG) and its membrane-permeable pro-drug derivative dimethyl-oxalylglycine (DMOG) have been extensively used as tools to study prolyl hydroxylases (PHDs) and other αKG-dependent processes. In cell culture media, DMOG is rapidly converted to MOG, which enters cells through monocarboxylate transporter MCT2, leading to intracellular NOG concentrations that are sufficiently high to inhibit glutaminolysis enzymes and cause cytotoxicity. Therefore, the degree of (D)MOG instability together with MCT2 expression levels determine the intracellular targets NOG engages with and, ultimately, its effects on cell viability. Here we designed and characterised a series of MOG analogues with the aims of improving compound stability and exploring the functional requirements for interaction with MCT2, a relatively understudied member of the SLC16 family. We report MOG analogues that maintain ability to enter cells via MCT2, and identify compounds that do not inhibit glutaminolysis or cause cytotoxicity but can still inhibit PHDs. We use these analogues to show that, under our experimental conditions, glutaminolysis-induced activation of mTORC1 can be uncoupled from PHD activity. Therefore, these new compounds can help deconvolute cellular effects that result from the polypharmacological action of NOG.rom the polypharmacological action of NOG.)
Horvath 2022 Antioxidants (Basel) + (α-ketoglutarate dehydrogenase complex (KGD … α-ketoglutarate dehydrogenase complex (KGDHc), or 2-oxoglutarate dehydrogenase complex (OGDHc) is a rate-limiting enzyme in the tricarboxylic acid cycle, that has been identified in neurodegenerative diseases such as in Alzheimer's disease. The aim of the present study was to establish the role of the KGDHc and its subunits in the bioenergetics and reactive oxygen species (ROS) homeostasis of brain mitochondria. To study the bioenergetic profile of KGDHc, genetically modified mouse strains were used having a heterozygous knock out (KO) either in the dihydrolipoyl succinyltransferase (DLST+/-) or in the dihydrolipoyl dehydrogenase (DLD+/-) subunit. Mitochondrial oxygen consumption, hydrogen peroxide (H2O2) production, and expression of antioxidant enzymes were measured in isolated mouse brain mitochondria. Here, we demonstrate that the ADP-stimulated respiration of mitochondria was partially arrested in the transgenic animals when utilizing α-ketoglutarate (α-KG or 2-OG) as a fuel substrate. Succinate and α-glycerophosphate (α-GP), however, did not show this effect. The H2O2 production in mitochondria energized with α-KG was decreased after inhibiting the adenine nucleotide translocase and Complex I (CI) in the transgenic strains compared to the controls. Similarly, the reverse electron transfer (RET)-evoked H2O2 formation supported by succinate or α-GP were inhibited in mitochondria isolated from the transgenic animals. The decrease of RET-evoked ROS production by DLST+/- or DLD+/- KO-s puts the emphasis of the KGDHc in the pathomechanism of ischemia-reperfusion evoked oxidative stress. Supporting this notion, expression of the antioxidant enzyme glutathione peroxidase was also decreased in the KGDHc transgenic animals suggesting the attenuation of ROS-producing characteristics of KGDHc. These findings confirm the contribution of the KGDHc to the mitochondrial ROS production and in the pathomechanism of ischemia-reperfusion injury.stics of KGDHc. These findings confirm the contribution of the KGDHc to the mitochondrial ROS production and in the pathomechanism of ischemia-reperfusion injury.)
Risiglione 2022 Life (Basel) + (α-synuclein (αSyn) is a small neuronal pro … α-synuclein (αSyn) is a small neuronal protein whose accumulation correlates with Parkinson's disease. αSyn A53T mutant impairs mitochondrial functions by affecting substrate import within the organelle, activity of complex I and the maximal respiratory capacity. However, the precise mechanism initiating the bioenergetic dysfunction is not clearly understood yet. By overexpressing αSyn A53T in SH-SY5Y cells, we investigated the specific changes in the mitochondrial respiratory profile using High-Resolution Respirometry. We found that αSyn A53T increases dissipative fluxes across the intermembrane mitochondrial space: this does not compromise the oxygen flows devoted to ATP production while it reduces the bioenergetic excess capacity of mitochondria, providing a possible explanation of the increased cell susceptibility observed in the presence of further stress stimuli.in the presence of further stress stimuli.)
Martinez 2018 Arch Biochem Biophys + (α-synuclein is involved in both familial a … α-synuclein is involved in both familial and sporadic Parkinson's disease. Although its interaction with mitochondria has been well documented, several aspects remain unknown or under debate such as the specific sub-mitochondrial localization or the dynamics of the interaction. It has been suggested that α-synuclein could only interact with ER-associated mitochondria. The vast use of model systems and experimental conditions makes it difficult to compare results and extract definitive conclusions. Here we tackle this by analyzing, in a simplified system, the interaction between purified α-synuclein and isolated rat brain mitochondria. This work shows that wild type α-synuclein interacts with isolated mitochondria and translocates into the mitochondrial matrix. This interaction and the irreversibility of α-synuclein translocation depend on incubation time and α-synuclein concentration. FRET experiments show that α-synuclein localizes close to components of the TOM complex suggesting a passive transport of α-synuclein through the outer membrane. In addition, α-synuclein binding alters mitochondrial function at the level of Complex I leading to a decrease in ATP synthesis and an increase of ROS production.nthesis and an increase of ROS production.)
Gregg 2019 J Biol Chem + (β-cell mitochondria play a central role in … β-cell mitochondria play a central role in coupling glucose metabolism with insulin secretion. Here, we identified a metabolic function of cyclin-dependent kinase 1 (CDK1)/cyclin B1 - the activation of mitochondrial respiratory Complex I - that is active in quiescent adult β-cells and hyperactive in β-cells from obese (''ob/ob'') mice. In wild-type islets, respirometry revealed that 65 % of Complex I flux and 49 % of state 3 respiration is sensitive to CDK1 inhibition. Islets from ''ob/ob'' mice expressed more cyclin B1 and exhibited a higher sensitivity to CDK1 blockade, which reduced Complex I flux by 76 % and state 3 respiration by 79 %. The ensuing reduction in mitochondrial NADH utilization, measured with 2-photon NAD(P)H fluorescence lifetime imaging (FLIM), was matched in the cytosol by a lag in citrate cycling, as shown with a FRET reporter targeted to β-cells. Moreover, time-resolved measurements revealed that in ''ob/ob'' islets, where Complex I flux dominates respiration, CDK1 inhibition is sufficient to restrict the duty cycle of ATP/ADP and calcium oscillations, the parameter that dynamically encodes β-cell glucose sensing. Direct Complex I inhibition with rotenone mimicked the restrictive effects of CDK1 inhibition on mitochondrial respiration, NADH turnover, ATP/ADP, and calcium influx. These findings identify Complex I as a critical mediator of obesity-associated metabolic remodeling in β-cells, and implicate CDK1 as a regulator of Complex I that enhances β-cell glucose sensing.Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Biochemistry and Molecular Biology, Inc.)
D'Onofrio 2020 Sci Rep + (δ-Valerobetaine (δVB) is a constitutive mi … δ-Valerobetaine (δVB) is a constitutive milk metabolite with antioxidant and anti-inflammatory activities. Here, we tested the antineoplastic properties of milk δVB on human colorectal cancer cells. CCD 841 CoN (non-tumorigenic), HT-29 (p53 mutant adenocarcinoma) and LoVo (APC/RAS mutant adenocarcinoma) cells were exposed to 3 kDa milk extract, δVB (2 mM) or milk+δVB up to 72 h. Results showed a time- and dose-dependent capability of δVB to inhibit cancer cell viability, with higher potency in LoVo cells. Treatment with milk+δVB arrested cell cycle in G2/M and SubG1 phases by upregulating p21, cyclin A, cyclin B1 and p53 protein expressions. Noteworthy, δVB also increased necrosis (P < 0.01) and when used in combination with milk it improved its activity on live cell reduction (P < 0.05) and necrosis (P < 0.05). δVB-enriched milk activated caspase 3, caspase 9, Bax/Bcl-2 apoptotic pathway and reactive oxygen species (ROS) production, whereas no effects on ROS generation were observed in CCD 841 CoN cells. The altered redox homeostasis induced by milk+δVB was accompanied by upregulation of sirtuin 6 (SIRT6). SIRT6 silencing by small interfering RNA blocked autophagy and apoptosis activated by milk+δVB, unveiling the role of this sirtuin in the ROS-mediated apoptotic LoVo cell death.tuin in the ROS-mediated apoptotic LoVo cell death.)
Gnaiger 2018 EBEC2018 + (‘.. ''the sum of the '''electrical pressur … ‘.. ''the sum of the '''electrical pressure difference''' and the '''osmotic pressure difference''' (i.e. the electrochemical potential difference) of protons''’ [1] links to non-ohmic flux-force relationships between proton leak and protonmotive force ''pmF''. This is experimentally established, has direct consequences on mitochondrial physiology, but is theoretically little understood [2,3]. Here I distinguish pressure from potential differences (diffusion: Δ''μ''H+ or Δd''F''H+; electric: Δ''Ψ'' or Δel''F''p+), to explain non-ohmic flux-'''[[force]]''' relationships on the basis of four thermodynamic theorems. (''1'') Einstein’s diffusion equation [4] explains the [[concentration]] gradient (d'''''c'''''/d'''''z''''') in Fick’s law as the product of chemical potential gradient (the vector force and resistance determine the velocity '''''v''''' of a particle) and local concentration '''''c'''''. This yields the chemical [[pressure]] gradient (van’t Hoff): d'''d''''''''Π'''''/d'''''z''''' = ''RT''∙d'''''c'''''/'''d''z'''''. [[Flux]] [5] is the product of '''''v''''' and '''''c'''''; '''''c''''' varies with force. Therefore, flux-force relationships are non-linear. (''2'') The ''pmF'' is not a vector force; the gradient is replaced by a pressure difference, and local concentration by a distribution function or free activity ''α''. Flux is a function of ''α'' and force, ''J''d = -''u''d∙''α''∙Δd''FX'' = -''u''d∙Δd''ΠX'' [6]. (''3'') At Δel''F''p+ = -Δd''F''H+, the diffusion pressure of protons, Δd''Π''H+ = ''RT''∙Δ''c''H+ [Pa=J∙m-3] is balanced by electric pressure, maintained by counterions of H+. Diffusional and electric pressures are isomorphic, additive, and yield protonmotive pressure ''pmp''. (''4'') The dependence of [[proton leak]] on ''pmF'' varies with Δel''F''p+ versus Δd''F''H+, in agreement with experimental evidence. The flux-force relationship is concave at high mitochondrial volume fractions, but near-exponential at small mt-matrix volume ratios. Linear flux-''pmp'' relationships imply a near-exponential dependence of the proton leak on the ''pmF'' ([7]; added 2022-07-04).t;sub>p+ versus Δd''F''H+, in agreement with experimental evidence. The flux-force relationship is concave at high mitochondrial volume fractions, but near-exponential at small mt-matrix volume ratios. Linear flux-''pmp'' relationships imply a near-exponential dependence of the proton leak on the ''pmF'' ([7]; added 2022-07-04).)
Gnaiger 2023 MiP2023 + (‘Obesity is a complex condition, one with … ‘Obesity is a complex condition, one with serious social and psychological dimensions, that affects virtually all age and socioeconomic groups and threatens to overwhelm both developed and developing countries’ ― the WHO perspective on ‘globesity’ (https://www.who.int/activities/controlling-the-global-obesity-epidemic). Obesity defined as [[BMI]]≥30 (WHO) is biased, overestimating obesity thresholds in taller persons (men) but underestimating it in smaller groups (women) ― a gender data gap. Here obesity is defined as accumulation of excess fat-tissue mass, ''M''FE=''M''F-''M''F°. ''M''F° is the fat mass per individual in the [[healthy reference population]] at any height and body mass ''M''° without overweight. Body fat excess, BFE=''M''FE/''M''°, is related to body mass excess, [[BME]]=''M''E/''M''°, where ''M''E=''M''-''M''°. A balanced BME is BME° = 0.0 with a band width of -0.1 towards underweight and +0.2 towards pre-obesity (overweight). The BME is linearly related to the body fat excess in women and men with statistical implications on mitochondrial functional fitness.[[File:MitObesity-and-comorbidities.jpg|500px|right|link=Category:BME_and_mitObesity|mitObesity]]Aerobic spiroergometric capacity per body mass ''V''O2max/''M'' and mitochondrial respiratory capacity per muscle mass [1] decline as a function of BME. Compromised mitochondrial fitness across metabolically active organs provides a functional connection between obesity and comorbidities bound to redox imbalance, inflammation, oxidative stress, and insulin resistance: diabetes, cardiovascular and neurodegenerative diseases, various types of cancer (Figure 1). mitObesity is the leading cause of deaths and early aging, prevented by improved quality of life in active lifestyles with exercise and caloric balance. Obesity has reached the general news, without connection to mitochondria. How do we get from globesity to mitObesity to forge scientific results into knowledge impacting society, health system stakeholders, and politics? ow do we get from globesity to mitObesity to forge scientific results into knowledge impacting society, health system stakeholders, and politics? )
Sies 2020 Nat Rev Mol Cell Biol + (‘Reactive oxygen species’ (ROS) is an umbr … ‘Reactive oxygen species’ (ROS) is an umbrella term for an array of derivatives of molecular oxygen that occur as a normal attribute of aerobic life. Elevated formation of the different ROS leads to molecular damage, denoted as ‘oxidative distress’. Here we focus on ROS at physiological levels and their central role in redox signalling via different post-translational modifications, denoted as ‘oxidative eustress’. Two species, hydrogen peroxide (H2O2) and the superoxide anion radical (O2·−), are key redox signalling agents generated under the control of growth factors and cytokines by more than 40 enzymes, prominently including NADPH oxidases and the mitochondrial electron transport chain. At the low physiological levels in the nanomolar range, H2O2 is the major agent signalling through specific protein targets, which engage in metabolic regulation and stress responses to support cellular adaptation to a changing environment and stress. In addition, several other reactive species are involved in redox signalling, for instance nitric oxide, hydrogen sulfide and oxidized lipids. Recent methodological advances permit the assessment of molecular interactions of specific ROS molecules with specific targets in redox signalling pathways. Accordingly, major advances have occurred in understanding the role of these oxidants in physiology and disease, including the nervous, cardiovascular and immune systems, skeletal muscle and metabolic regulation as well as ageing and cancer. In the past, unspecific elimination of ROS by use of low molecular mass antioxidant compounds was not successful in counteracting disease initiation and progression in clinical trials. However, controlling specific ROS-mediated signalling pathways by selective targeting offers a perspective for a future of more refined redox medicine. This includes enzymatic defence systems such as those controlled by the stress-response transcription factors NRF2 and nuclear factor-κB, the role of trace elements such as selenium, the use of redox drugs and the modulation of environmental factors collectively known as the exposome (for example, nutrition, lifestyle and irradiation).le, nutrition, lifestyle and irradiation).)
Aoun 2015 Abstract MiP2015 + (“Neurodegeneration with brain iron accumul … “Neurodegeneration with brain iron accumulation” (NBIA) comprises a group of progressive neurodegenerative disorders characterized by high content of iron in the brain. Mutations in PANK2 gene, which encodes for the mitochondrial protein pantothenate kinase type 2, determine an autosomal recessive inborn error of CoA metabolism, called pantothenate kinase-associated neurodegeneration (PKAN). The pathogenesis of PKAN, the most frequent form of NBIA, is still poorly understood. [1]In our study, we are exploring a Pank2-KO mice model, which showed altered mitochondria membrane potential in neurons and defective respiration in the brain. Moreover, we have demonstrated that ketogenic diet, which stimulates lipid utilization by mitochondrial beta-oxidation, was able to reveal a clinical phenotype not present in Pank2-KO mice under standard diet [2]. These mitochondrial bioenergetics failure due to the absence of PANK2 protein may result from defects in mitochondrial membrane integrity and consequently in supercomplexes stabilization. Our first results showed a deficiency in complex IV activity in supercomplexes in the brain from Pank2-KO mice. In fact, PANK2 by synthesizing CoA required for membrane phospholipids remodeling and repair, indirectly contributes to the synthesis of cardiolipin implicated in supercomplexes stabilization. Thus, phospholipids metabolism could be an interesting target to better explore membrane homeostasis ''in vivo''.In parallel, we are conducting lipidomic analysis on NBIA patients fibroblasts and on PKAN patients red blood cells (RBC). The fibroblasts are an interesting tool to explore lipid metabolism in these diseases. Moreover, the complexity of the blood lipids profile establishes it as a rich source of molecules that can provide clues about human physiology and disease. Our first results showed a difference in fatty acids lipogenesis in fibroblasts and in phospholipids distribution in RBC membranes, mainly a decrease in phosphatidylcholine and sphingomyelin. Thus, lipidomic analysis in NBIA patients’ fibroblasts and RBC could provide a powerful biomarker in clinical medicine to understanding lipid biology in NBIA pathogenesis and monitoring therapeutic intervention.s and monitoring therapeutic intervention.)
Skulachev 2013 Abstract MiP2013 + (“One can qualify himself as a physiologist … “One can qualify himself as a physiologist only if he succeeded in normalizing a physiological process damaged by a pathology” (IP Pavlov)In this group, a concept was put forward considering mitochondrial reactive oxygen species (mtROS) as key intermediates of programmed aging of organism. As a consequence of such a concept, it was suggested that aging program can be retarded (or even switched off) by mitochondria-targeted antioxidants [5]. To this end, 10-(6’-plastoquinonyl) decyltriphenyl phosphonium cation (SkQ1) was synthesized. It was shown that SkQ1 (i) is good penetrant for model and mitochondrial membranes, (ii) has very high affinity to membranes, (iii) is reduced by center i of respiratory Complex III in the inner leaflet of the inner mitochondrial membrane, (vi) electrophoretically accumulates in this leaflet, being driven by the mitochondrial membrane potential, (v) prevents peroxidation of mitochondrial cardiolipin by mtROS, (vi) arrests the ROS-induced apoptosis and necrosis, (vii) prolongs the lifespan of various organisms (from fungi and plants to mammals), and (viii) retards development of many traits of age-related diseases [1-6]. In particular, it was found that drops of SkQ1 instillated to eyes of rats prevent aging of tear glands, an effect leading to cure of such a disease as the dry eye syndrome which is usually assumed to be incurable and can result in uveitis. Clinical trials of drops of 250 nM SkQ1 solution called “Visomitin” showed that the three-week treatment (3 drops per day) completely cure the dry eye syndrome in 60% patients. The following favorable changes were shown: an increase in the amount of tears, stability of tear film, acuity of vision as well as disappearance of inflammation in the eye tissues [7]. Drops of Visomitin are available in drugstores of Moscow and other places of Russia since July, 2012. By May 12, 2013, about 50 000 samples of the SkQ1 drops were sold and no claims concerning an unfavorable side effect were sent to the producers. Clinical trials of Visomitin as potential medicine to treat two other age-related eye diseases, namely cataract and glaucoma, were completed. For one of them (cataract), results are already available. In particular, it was found that acuity of vision was increased in 80.5% cataract patients ≥ 70 years. Preclinical trials of SkQ1 in treatment of the dry eye syndrome and uveitis were originally performed in Russia and are now confirmed in three laboratories in the USA (Ora Inc., Andover; Toxikon Corp., Minneapolis; Comparative Biosciences Inc., Sunny Vale). In the next future, clinical trials of Visomitin will start in the USA.trials of Visomitin will start in the USA.)
Franca 2019 Learn Pub + (• Although there is no unique scientific m … • Although there is no unique scientific method, there are general requirementsthat reports of empirical evidence must fulfil in order to be useful.• Enforcing general requirements can improve the quality of published studieswithout promoting a narrowly defined scientific method that would limit thescope of science.• The reproducibility movement advises against using novelty as the main requirementfor publication and promotes the enforcement of transparent reportingand rigorous peer review.• Novelty is important for science but must not be the sole requirement for publicationdecisions as this can lead to publication bias and seriously distort the scientificliterature.• While the scientific community remains responsible for thoroughly evaluatingpublished papers, strengthening the peer review process will help to improvetransparency and replicability.to improve transparency and replicability.)