Mitochondrial Electron Transport System Research Articles

Mitochondrial puzzle in muscle: Linking the electron transport system to overweight.

Human skeletal muscle mitochondria regulate energy expenditure. Research has shown that the functionality of muscle mitochondria is altered in subjects with overweight, as well as in response to nutrient excess and calorie restriction. Two metabolic features of obesity and overweight are (1) incomplete muscular fatty acid oxidation and (2) increased circulating lactate levels. In this study, I propose that these metabolic disturbances may originate from a common source within the muscle mitochondrial electron transport system. Specifically, a reorganization of the supramolecular structure of the electron transport chain could facilitate the maintenance of readily accessible coenzyme Q pools, which are essential for metabolizing lipid substrates. This approach is expected to maintain effective electron transfer, provided that there is sufficient complex III to support the Q-cycle. Such an adaptation could enhance fatty acid oxidation and prevent mitochondrial overload, thereby reducing lactate production. These insights advance our understanding of the molecular mechanisms underpinning metabolic dysregulation in overweight states. This provides a basis for targeted interventions in the quest for metabolic health.

Effect of Orally Ingested Water Containing H2-Filled Ultrafine Bubbles (UFBs) on Ethanol-Induced Oxidative Stress in Rats.

Ultrafine bubbles (UFBs), which are bubbles with diameters of less than 1 µm, are widely recognized for their ability to exist stably in liquid as a result of the effects of Brownian motion. In this study, we focused on hydrogen, known for its antioxidant potential, and explored the function of H2-filled UFBs, which encapsulate hydrogen, to determine their potential use as oral carriers for the delivery bioactive gases to living organisms. To this end, rats were orally administered ethanol to induce hepatic oxidative stress, and the effects of drinking H2-filled UFBs (H2 NanoGAS®) water for two weeks were evaluated to assess the reduction of oxidative stress. Continuous alcohol consumption was found to significantly increase the blood lipid peroxidation levels in the control group, confirming the induction of oxidative stress. An increase in blood lipid peroxidation was significantly inhibited by the consumption of concentrated H2 NanoGAS® (C-HN) water. Furthermore, the measurement of mitochondrial activity in the liver revealed that drinking H2 NanoGAS® water helped to maintain at a normal level and/or boosted the functional activity of the electron transport system in mitochondria affected by ethanol intake. To our knowledge, this study is the first to provide evidence for the use of orally ingested UFBs as carriers for the delivery gases to tissues, thereby exerting their physiological activity in the body. Our findings highlight the potential for the application of UFBs to various physiologically active gases and their utilization in the medical field in the future.

Effects of nano-TiO2 and pentachlorophenol on the bioenergetics of mussels under predatory stress

Organic and nanoparticle pollutants are the main environmental problems affecting marine species, which have received great attention. However, the combined effect of pollutants on marine life in the presence of predators needs to be clarified. In this study, the effects of pentachlorophenol (PCP) and titanium dioxide nanoparticles (nano-TiO2) on the energy metabolism of mussels (Mytilus coruscus) in the presence of predators were assessed through cellular energy allocation (CEA) approach. Mussels were exposed to PCP (0, 1, and 10 μg/L), nano-TiO2 (1 mg/L, 25 and 100 nm), and predators (Portunus trituberculatus presence/absence) for 14 days. Exposure to high concentrations of PCP (10 μg/L) with small particle size nano-TiO2 (25 nm) decreased cellular energy stores (carbohydrates, lipids, and proteins) and increased cellular energy demand (measured as the activity of the mitochondrial electron transport system, ETS). During the first 7 days, energy was supplied mainly through the consumption of carbohydrates, while lipids are mobilized to participate after 7 days. The presence of predators caused a further decrease in energy stores. These findings demonstrate that PCP, nano-TiO2 and predators have a negative impact on energy metabolism at the cellular level. Carbohydrates are not able to meet the metabolic demand, lipids need to be consumed, and energy metabolism was also mediated by the involvement of proteins. Overall, our results suggest that PCP, nano-TiO2 and predators disrupt the cellular energy metabolism of mussels through reduced cellular energy allocation, small particles and predators drive mussels to exert energetic metabolic adjustments for detoxification reactions when toxic contaminants are present.

CoQ10 and Mitochondrial Dysfunction in Alzheimer's Disease.

The progress in understanding the pathogenesis and treatment of Alzheimer's disease (AD) is based on the recognition of the primary causes of the disease, which can be deduced from the knowledge of risk factors and biomarkers measurable in the early stages of the disease. Insights into the risk factors and the time course of biomarker abnormalities point to a role for the connection of amyloid beta (Aβ) pathology, tau pathology, mitochondrial dysfunction, and oxidative stress in the onset and development of AD. Coenzyme Q10 (CoQ10) is a lipid antioxidant and electron transporter in the mitochondrial electron transport system. The availability and activity of CoQ10 is crucial for proper mitochondrial function and cellular bioenergetics. Based on the mitochondrial hypothesis of AD and the hypothesis of oxidative stress, the regulation of the efficiency of the oxidative phosphorylation system by means of CoQ10 can be considered promising in restoring the mitochondrial function impaired in AD, or in preventing the onset of mitochondrial dysfunction and the development of amyloid and tau pathology in AD. This review summarizes the knowledge on the pathophysiology of AD, in which CoQ10 may play a significant role, with the aim of evaluating the perspective of the pharmacotherapy of AD with CoQ10 and its analogues.

Effect of skeletal muscle mitochondrial phenotype on H2O2 emission

Reactive oxygen species (ROS) are a key output of the skeletal muscle mitochondrial information processing system both at rest and during exercise. In skeletal muscle, mitochondrial ROS release depends on multiple factors; however, fiber-type specific differences remain ambiguous in part owing to the use of mitochondria from mammalian muscle that consist of mixed fibers. To elucidate fiber-type specific differences, we used mitochondria isolated from rainbow trout (Oncorhynchus mykiss) red and white skeletal muscles that consist of spatially distinct essentially pure red and white fibers. We first characterized the assay conditions for measuring ROS production (as H2O2) in isolated fish red and white skeletal muscle mitochondria (RMM and WMM) and thereafter compared the rates of emission during oxidation of different substrates and the responses to mitochondrial electron transport system (ETS) pharmacological modulators. Our results showed that H2O2 emission rates by RMM and WMM can be quantified using the same protein concentration and composition of the Amplex UltraRed-horseradish peroxidase (AUR-HRP) detection system. For both RMM and WMM, protein normalized H2O2 emission rates were highest at the lowest protein concentration tested and decreased exponentially thereafter. However, the absolute values of H2O2 emission rates depended on the calibration curves used to convert fluorescent signals to H2O2 while the trends depended on the normalization strategy. We found substantial qualitative and quantitative differences between RMM and WMM in the H2O2 emission rates depending on the substrates being oxidized and their concentrations. Similarly, pharmacological modulators of the ETS altered the magnitudes and trends of the H2O2 emission differently in RMM and WMM. While comparable concentrations of substrates elicited maximal albeit quantitively different emission rates in RMM and WMM, different concentrations of pharmacological ETS modulators may be required for maximal H2O2 emission rates depending on muscle fiber-type. Taken together, our study suggests that biochemical differences exist in RMM compared with WMM that alter substrate oxidation and responses to ETS modulators resulting in fiber-type specific mitochondrial H2O2 emission rates.

Nanosecond Pulsed Electric Fields (nsPEFs) Modulate Electron Transport in the Plasma Membrane and the Mitochondria

Nanosecond pulsed electric fields (nsPEFs) are a pulsed power technology known for ablating tumors, but they also modulate diverse biological mechanisms. Here we show that nsPEFs regulate trans-plasma membrane electron transport (tPMET) rates in the plasma membrane redox system (PMRS) shown as a reduction of the cell-impermeable, WST-8 tetrazolium dye. At lower charging conditions, nsPEFs enhance, and at higher charging conditions inhibit tPMET in H9c2 non-cancerous cardiac myoblasts and 4T1-luc breast cancer cells. This biphasic nsPEF-induced modulation of tPMET is typical of a hormetic stimulus that is beneficial and stress-adaptive at lower levels and damaging at higher levels. NsPEFs also attenuated mitochondrial electron transport system (ETS) activity (O2 consumption) at Complex I when coupled and uncoupled to oxidative phosphorylation. NsPEFs generated more reactive oxygen species (ROS) in mitochondria (mROS) than in the cytosol (cROS) in non-cancer H9c2 heart cells but more cROS than mROS in 4T1-luc cancer cells. Under lower charging conditions, nsPEFs support glycolysis while under higher charging conditions, nsPEFs inhibit electron transport in the PMRS and the mitochondrial ETS producing ROS, ultimately causing cell death. The impact of nsPEF on ETS presents a new paradigm for considering nsPEF modulation of redox functions, including redox homeostasis and metabolism.

Metabolic adaptation of human skin fibroblasts to ER stress caused by glycosylation defect in PMM2-CDG.

PMM2-CDG is the most prevalent type of congenital disorders of glycosylation (CDG). It is caused by pathogenic variants in the gene encoding phosphomannomutase 2 (PMM2), which converts mannose-6-phosphate to mannose-1-phosphate and thus activates this saccharide for further glycosylation processes. Defective glycosylation can lead to an abnormal accumulation of unfolded proteins in endoplasmic reticulum (ER) and cause its stress. The ER is a key compartment for glycosylation, and its connection and communication with mitochondria has been described extensively in literature. Their crosstalk is important for cell proliferation, calcium homeostasis, apoptosis, mitochondrial fission regulation, bioenergetics, autophagy, lipid metabolism, inflammasome formation and unfolded protein response. Therefore, in the present study we posed a question, whether defective glycosylation leads to bioenergetic disruption. Our data reveal possible chronic stress in ER and activated unfolded protein response via PERK pathway in PMM2-CDG fibroblasts. Presumably, it leads to bioenergetic reorganization and increased assembly of respiratory chain complexes into supercomplexes together with suppressed glycolysis in PMM2-CDG patient cells. These changes cause alterations in Krebs cycle, which is tightly connected to electron transport system in mitochondria. In summary, we present data showing metabolic adaptation of cells to glycosylation defect caused by various pathogenic variants in PMM2.

Bypassing mitochondrial defects rescues Huntington's phenotypes in Drosophila

Huntington's disease (HD) is a fatal neurodegenerative disease with limited treatment options. Human and animal studies have suggested that metabolic and mitochondrial dysfunctions contribute to HD pathogenesis. Here, we use high-resolution respirometry to uncover defective mitochondrial oxidative phosphorylation and electron transfer capacity when a mutant huntingtin fragment is targeted to neurons or muscles in Drosophila and find that enhancing mitochondrial function can ameliorate these defects. In particular, we find that co-expression of parkin, an E3 ubiquitin ligase critical for mitochondrial dynamics and homeostasis, produces significant enhancement of mitochondrial respiration when expressed either in neurons or muscles, resulting in significant rescue of neurodegeneration, viability and longevity in HD model flies. Targeting mutant HTT to muscles results in larger mitochondria and higher mitochondrial mass, while co-expression of parkin increases mitochondrial fission and decreases mass. Furthermore, directly addressing HD-mediated defects in the fly's mitochondrial electron transport system, by rerouting electrons to either bypass mitochondrial complex I or complexes III-IV, significantly increases mitochondrial respiration and results in a striking rescue of all phenotypes arising from neuronal mutant huntingtin expression. These observations suggest that bypassing impaired mitochondrial respiratory complexes in HD may have therapeutic potential for the treatment of this devastating disorder.

Effect of Simvastatin Treatment on Mitochondrial Function and Inflammatory Status of Human White Adipose Tissue.

Statin therapy has shown pleiotropic effects affecting both mitochondrial function and inflammatory status. However, few studies have investigated the concurrent effects of statin exposure on mitochondrial function and inflammatory status in human subcutaneous white adipose tissue. In a cross-sectional study, we investigated the effects of simvastatin on mitochondrial function and inflammatory status in subcutaneous white adipose tissue of 55 human participants: 38 patients (19 females/19 males) in primary prevention with simvastatin (> 40 mg/d, > 3 mo) and 17 controls (9 females/8 males) with elevated plasma cholesterol. The 2 groups were matched on age, body mass index, and maximal oxygen consumption. Anthropometrics and fasting biochemical characteristics were measured. Mitochondrial respiratory capacity was assessed in white adipose tissue by high-resolution respirometry. Subcutaneous white adipose tissue expression of the inflammatory markers IL-6, chemokine (C-C motif) ligand 2 (CCL2), CCL-5, tumor necrosis factor-α, IL-10, and IL-4 was analyzed by quantitative PCR. Simvastatin-treated patients showed lower plasma cholesterol (P < .0001), low-density lipoprotein (P < .0001), and triglyceride levels (P = .0116) than controls. Simvastatin-treated patients had a lower oxidative phosphorylation capacity of mitochondrial complex II (P = .0001 when normalized to wet weight, P < .0001 when normalized to citrate synthase activity [intrinsic]), and a lower intrinsic mitochondrial electron transport system capacity (P = .0004). Simvastatin-treated patients showed higher IL-6 expression than controls (P = .0202). Simvastatin treatment was linked to mitochondrial respiratory capacity in human subcutaneous white adipose tissue, but no clear link was found between statin exposure, respiratory changes, and inflammatory status of adipose tissue.

Electron transfer and ROS production in brain mitochondria of intertidal and subtidal triplefin fish (Tripterygiidae)

While oxygen is essential for oxidative phosphorylation, O2 can form reactive species (ROS) when interacting with electrons of mitochondrial electron transport system. ROS is dependent on O2 pressure (PO2) and has traditionally been assessed in O2 saturated media, PO2 at which mitochondria do not typically function in vivo. Mitochondrial ROS can be significantly elevated by the respiratory complex II substrate succinate, which can accumulate within hypoxic tissues, and this is exacerbated further with reoxygenation. Intertidal species are repetitively exposed to extreme O2 fluctuations, and have likely evolved strategies to avoid excess ROS production. We evaluated mitochondrial electron leakage and ROS production in permeabilized brain of intertidal and subtidal triplefin fish species from hyperoxia to anoxia, and assessed the effect of anoxia reoxygenation and the influence of increasing succinate concentrations. At typical intracellular PO2, net ROS production was similar among all species; however at elevated PO2, brain tissues of the intertidal triplefin fish released less ROS than subtidal species. In addition, following in vitro anoxia reoxygenation, electron transfer mediated by succinate titration was better directed to respiration, and not to ROS production for intertidal species. Overall, these data indicate that intertidal triplefin fish species better manage electrons within the ETS, from hypoxic–hyperoxic transitions.

Oral administration of ginseng berry concentrate improves lactate metabolism and increases endurance performance in mice

In the present study, to determine the efficacy of oral supplementation of ginseng berry extracts in augmenting exercise performance and exercise-associated metabolism, male mice were given orally 200 and 400 milligrams per kilogram of body weight (mpk) of GBC for seven weeks. Although there are no differences in pre-exercise blood lactate levels among (1) the control group that received neither exercise nor GBC, (2) the group that performed only twice-weekly endurance exercise, and (3 and 4) the groups that combined twice-weekly endurance exercise with either 200 or 400 mpk GBC, statistically significant reductions in post-exercise blood lactate levels were observed in the groups that combined twice-weekly endurance exercise with oral administration of either 200 or 400 mpk GBC. Histological analysis showed no muscle hypertrophy, but transcriptome analysis revealed changes in gene sets related to lactate metabolism and mitochondrial function. GBC intake increased nicotinamide adenine dinucleotide levels in the gastrocnemius, possibly enhancing the mitochondrial electron transport system and lactate metabolism. Further molecular mechanisms are needed to confirm this hypothesis.

NOX4 as a critical effector mediating neuroinflammatory cytokines, myeloperoxidase and osteopontin, specifically in astrocytes in the hippocampus in Parkinson's disease

Oxidative stress and mitochondrial dysfunction have been believed to play an important role in the pathogenesis of aging and neurodegenerative diseases, including Parkinson's disease (PD). The excess of reactive oxygen species (ROS) increases with age and causes a redox imbalance, which contributes to the neurotoxicity of PD. Accumulating evidence suggests that NADPH oxidase (NOX)-derived ROS, especially NOX4, belong to the NOX family and is one of the major isoforms expressed in the central nervous system (CNS), associated with the progression of PD. We have previously shown that NOX4 activation regulates ferroptosis via astrocytic mitochondrial dysfunction. We have previously shown that activation of NOX4 regulates ferroptosis through mitochondrial dysfunction in astrocytes. However, it remains unclear why an increase in NOX4 in neurodegenerative diseases leads to astrocyte cell death by certain mediators. Therefore, this study was designed to evaluate how NOX4 in the hippocampus is involved in PD by comparing an MPTP-induced PD mouse model compared to human PD patients. We could detect that the hippocampus was dominantly associated with elevated levels of NOX4 and α-synuclein during PD and the neuroinflammatory cytokines, myeloperoxidase (MPO) and osteopontin (OPN), were upregulated particularly in astrocytes. Intriguingly, NOX4 suggested a direct intercorrelation with MPO and OPN in the hippocampus. Upregulation of MPO and OPN induces mitochondrial dysfunction by suppressing five protein complexes in the mitochondrial electron transport system (ETC) and increases the level of 4-HNE leading to ferroptosis in human astrocytes. Overall, our findings indicate that the elevation of NOX4 cooperated with the MPO and OPN inflammatory cytokines through mitochondrial aberration in hippocampal astrocytes during PD.

Aerobic respiration, biochemical composition, and glycolytic responses to ultraviolet radiation in jellyfish Cassiopea sp

The light-dependent zooxanthellate jellyfish Cassiopea sp. (the upside-down jellyfish) is invasive/exotic in many shallow and clear marine habitats, where the jellyfish might be exposed to high levels of ultraviolet radiation (UVR). Compared to other reef organisms, the sensitivity/resilience of the semi-transparent jellyfish to UVR exposure is overlooked. Therefore, we experimentally investigated the metabolic and physiological responses of Cassiopea sp. from the Red Sea to natural levels of underwater UVR following 16 days of exposure to three light treatments: 1) control group with only photosynthetically active radiation (PAR), 2) PAR+UV-B, and 3) PAR+UV-B+UV-A. While jellyfish body mass increased (by 40%) significantly in the control group, it did not increase in either of the UV treatments. However, both UV-exposed jellyfish had higher (98% to 120%) mitochondrial electron transport system (ETS) activity than the control group. Therefore, the results indicate elevated aerobic respiration rates in UV-exposed jellyfish (i.e., reflecting a higher energy cost of UVR exposure). Neither the lactate dehydrogenase (LDH) activity nor the available energy (Ea) exhibited different levels among UVR treatments compared to the control group. In contrast, pyruvate kinase activity was significantly lower (by 46%) in all UV-exposed jellyfish compared to the control group. Unchanged Ea and LDH activity combined with higher ETS activity indicates a high aerobic capacity of jellyfish, which might explain their ability to cope with UVR exposure-induced higher energy demands without inducing the onset of anaerobiosis. The results indicated that UV-A does not amplify or modulate jellyfish physiology and growth under UV-B exposure. In conclusion, the findings suggest that the jellyfish is more resilient (i.e., in terms of survival) to UVR than other cnidarians. This study on Cassiopea is the first to address its metabolic and physiological responses to UVR. Therefore, it could be used as a framework for further studies aiming to better understand jellyfish physiology.

Comparative proteomics study of mitochondrial electron transport system modulation in SH-SY5Y cells following MPP+ versus 6-OHDA-induced neurodegeneration

Parkinson’s disease (PD) is the second-most common neurodegenerative disease worldwide. Several studies have investigated PD for decades; however, the exact mechanism of disease development remains unknown. To study PD, SH-SY5Y cells are often treated with 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenylpyridinium (MPP+) to induce PD. To understand the mechanism of PD pathogenesis, we confirmed protein changes between 6-OHDA- and MPP+-treated SH-SY5Y cells via proteomics analysis using liquid chromatography coupled with tandem mass spectrometry. 6-OHDA-treated SH-SY5Y cells showed increased expression of electron transporter-related proteins compared to that in the control group, along with decreased expression in MPP+-treated SH-SY5Y cells. However, both down- and upregulation of electron transporter-related proteins increased mitochondrial dysfunction and apoptosis. These proteins were confirmed via protein–protein interaction network analysis using IPA and STRING to induce mitochondrial dysfunction and apoptosis. Cell-based experiments using flow cytometry verified that apoptosis and mitochondrial membrane potential were increased in both 6-OHDA- and MPP+-treated SH-SY5Y cells. Our results provide new insights into PD pathogenesis, thereby contributing to the understanding of the mechanisms of PD development.

Transferrin, insulin, and progesterone modulate intracellular concentrations of coenzyme Q and cholesterol, products of the mevalonate pathway, in undifferentiated PC12 cells.

Coenzyme Q (CoQ) is important not only as an essential lipid for the mitochondrial electron transport system, but also as an antioxidant. CoQ levels decrease during aging and in various diseases. Orally administered CoQ is not readily taken up in the brain, so it is necessary to develop a method to increase the amount of CoQ in neurons. CoQ is synthesized via mevalonate pathway, like cholesterol. Transferrin, insulin, and progesterone are factors used in the culture of neurons. In this study, we determined the effect of these reagents on cellular CoQ and cholesterol levels. The administration of transferrin, insulin, and progesterone increased cellular CoQ levels in undifferentiated PC12 cells. When serum was removed and only insulin was administered, intracellular CoQ levels increased. This increase was even more pronounced with concurrent administration of transferrin, insulin, and progesterone. Cholesterol level decreased by the administration of transferrin, insulin, and progesterone. Progesterone treatment lowered intracellular cholesterol levels in a concentration-dependent manner. Our findings suggest that transferrin, insulin, and progesterone may be useful in regulating CoQ levels and cholesterol levels, which are products of the mevalonate pathway.

Abstract 203: Exploratory Study Of The Time Course Of Post-arrest Neurologic Injury In A Porcine Model Of Pediatric Cardiac Arrest

Introduction: In preclinical models, hemodynamic-directed CPR (HD-CPR) mitigates post-arrest neurofunctional impairment and cerebral mitochondrial dysfunction. We aimed to explore the temporal evolution of markers of neurologic injury over five days following cardiac arrest treated with HD-CPR. Methods: Pigs (1-month-old) underwent 7min asphyxia, induction of ventricular fibrillation, 10-20min of HD-CPR (goal SBP 90 mmHg, coronary perfusion pressure 20mmHg), randomization to post-ROSC survival duration (24, 48, 72, 96, 120h; n=3 per group) with standardized post-resuscitation care. Plasma neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) were collected at 0, 6, 24, 48, 72, 96, 120h and compared by mixed effects analysis. At terminal endpoints, cerebral cortical tissue was assessed for: mitochondrial electron transport system function; citrate synthase quantification (mitochondrial mass); immunoblot quantification of mitochondrial dynamic proteins (Opa-1, MFN-2, DRP-1, FIS-1); ELISA for 4-HNE and protein carbonyls (oxidative injury); and neuropathologic examination for IBA-1 (microglial activation) and GFAP (reactive astrocytes), all compared via ANOVA. Results: All animals had swine cerebral performance category score of 1 (grossly normal) by 24h after injury. Plasma NFL was significantly elevated at 24, 48, 72, 96 (p&lt;0.001) and 120h (p=0.009) compared to baseline. No significant differences were identified between time points for GFAP, mitochondrial measures, or neuropathological outcomes. Discussion: Despite grossly normal neurofunctional status, plasma NFL was elevated from baseline at multiple timepoints. No significant temporal differences were identified in other markers of neurologic injury. NFL may be a sensitive marker of mild neurologic injury post-arrest.

Preclinical and Clinical Role of Coenzyme Q10 Supplementation in Various Pathological States.

Coenzyme Q10 (CoQ10) is an efficient antioxidant produced endogenously in a living organism. It acts as an important cofactor in the electron transport system of mitochondria and reported as a safe supplement in humans and animals with minimal adverse effect. CoQ10 is found naturally, as a trans configuration, chemical nomenclature of which is 2,3- dimethoxy-5- methyl-6-decaprenyle -1,4-benzoquinone. It is found in the body in two forms. In quinone form (oxidized form), it serves as an electron transporter that transfers the electrons in the electron transport chain between various complexes, and in ubiquinol form (reduced form), it serves as potent antioxidants by scavenging free radicals or by tocopherol regeneration in the living organism. Its primary roles include synthesis of adenosine triphosphate (ATP), stabilizes lipid membrane, antioxidant activity, cell growth stimulation, and cell death inhibition. CoQ10 has shown a variety of pharmacological and clinical effects including neuroprotective, hepatoprotective, anti-atherosclerotic, anticonvulsant, antidepressant, anti-inflammatory, antinociceptive, cardiovascular, antimicrobial, immunomodulatory, and various effects on the central nervous system. Present review has set about to bring updated information regarding to clinical and preclinical activities of CoQ10, which may be helpful to researchers to explore a new bioactive molecules for various therapeutic application.

Evidence for a novel, effective approach to targeting carcinoma catabolism exploiting the first-in-class, anti-cancer mitochondrial drug, CPI-613.

Clinical targeting of the altered metabolism of tumor cells has long been considered an attractive hypothetical approach. However, this strategy has yet to perform well clinically. Metabolic redundancy is among the limitations on effectiveness of many approaches, engendering intrinsic single-agent resistance or efficient evolution of such resistance. We describe new studies of the multi-target, tumor-preferential inhibition of the mitochondrial tricarboxylic acid (TCA) cycle by the first-in-class drug CPI-613® (devimistat). By suppressing the TCA hub, indispensable to many metabolic pathways, CPI-613 substantially reduces the effective redundancy of tumor catabolism. This TCA cycle suppression also engenders an apparently homeostatic accelerated, inefficient consumption of nutrient stores in carcinoma cells, eroding some sources of drug resistance. Nonetheless, sufficiently abundant, cell line-specific lipid stores in carcinoma cells are among remaining sources of CPI-613 resistance in vitro and during the in vivo pharmacological drug pulse. Specifically, the fatty acid beta-oxidation step delivers electrons directly to the mitochondrial electron transport system (ETC), by-passing the TCA cycle CPI-613 target and producing drug resistance. Strikingly, tested carcinoma cell lines configure much of this fatty acid flow to initially traverse the peroxisome enroute to additional mitochondrial beta-oxidation. This feature facilitates targeting as clinically practical agents disrupting this flow are available. Two such agents significantly sensitize an otherwise fully CPI-613-resistant carcinoma xenograft in vivo. These and related results are strong empirical support for a potentially general class of strategies for enhanced clinical targeting of carcinoma catabolism.

NOR‐1 Knockdown Reduces Mitochondrial Function in C2C12 Myotubes

IntroductionSkeletal muscle is critical for whole‐body metabolic health and a prime determinant of quality of life. Mitochondrial health is compromised by several pathological states that alter muscle metabolism. Exercise is among the most effective means of preserving muscle mitochondrial health, yet rigorous exercise is often impossible in patients suffering from muscle‐related pathologies. Thus, the investigation of exercise responsive molecular targets is a requisite to identify therapeutics that improve muscle metabolic health. Neuron‐derived orphan receptor‐1 (NOR‐1) is highly responsive to exercise and is reduced in preclinical models of obesity and diabetes. The objective of the current study was to investigate the impact of NOR‐1 loss on C2C12 metabolic signaling. We hypothesized that knockdown (KD) of NOR‐1 in myotubes would perturb mitochondrial‐associated gene expression.MethodsC2C12 myotubes were transfected with control or NOR‐1 targeting siRNA to knock down NOR‐1. Protein and RNA were isolated from cells for immunoblotting and qPCR analysis, respectively. Cells were also stained with JC‐1 to evaluate alterations in mitochondrial membrane potential (MMP). NAD+ and NADH+ content was also measured in myotubes. Gene expression was normalized to ß‐actin mRNA whereas protein levels were normalized to total protein. Data were analyzed by an unpaired T‐Test with significance set at p &lt; 0.05 and presented as means ± SEM.ResultsNOR‐1 KD cells had lower gene expression of PGC‐1α, TFAM, and MFN2 and several proteins involved in energy production were altered (ND2, CYCS, CPT‐1ß, FABP4). Myosin protein content and gene expression of MYHI, MYHIIA, and MYHIIX were also reduced. Protein abundance of mitochondrial electron transport system complexes were reduced and both BAX and DRP1 abundance were enhanced after NOR‐1 KD, which was coincident with a diminished NADH content, and a shift towards the green monomeric spectra after JC‐1 staining, indicating a reduced mitochondrial membrane potential. Surprisingly, NOR‐1 KD also reduced mTORC1 signaling, evidenced by reduced P70S6K and S6K phosphorylation.ConclusionsThese data suggest loss of NOR‐1 reduces oxidative gene expression, induces mitochondrial depolarization, and reduces NADH content, implicating NOR‐1 as an important regulator of energy homeostasis and muscle metabolic signaling. Investigations into the molecular hierarchy between NOR‐1 and PGC‐1α will delineate between primary and secondary effects of NOR‐1 deficiency.

Presence of Phylloquinone in the Intraerythrocytic Stages of Plasmodium falciparum.

Malaria is one of the most widespread parasitic diseases, especially in Africa, Southeast Asia and South America. One of the greatest problems for control of the disease is the emergence of drug resistance, which leads to a need for the development of new antimalarial compounds. The biosynthesis of isoprenoids has been investigated as part of a strategy to identify new targets to obtain new antimalarial drugs. Several isoprenoid quinones, including menaquinone-4 (MK-4/vitamin K2), α- and γ-tocopherol and ubiquinone (UQ) homologs UQ-8 and UQ-9, were previously detected in in vitro cultures of Plasmodium falciparum in asexual stages. Herein, we described for the first time the presence of phylloquinone (PK/vitamin K1) in P. falciparum and discuss the possible origins of this prenylquinone. While our results in metabolic labeling experiments suggest a biosynthesis of PK prenylation via phytyl pyrophosphate (phytyl-PP) with phytol being phosphorylated, on the other hand, exogenous PK attenuated atovaquone effects on parasitic growth and respiration, showing that this metabolite can be transported from extracellular environment and that the mitochondrial electron transport system (ETS) of P. falciparum is capable to interact with PK. Although the natural role and origin of PK remains elusive, this work highlights the PK importance in plasmodial metabolism and future studies will be important to elucidate in seeking new targets for antimalarial drugs.