Search

Communication by rare, binary spikes is a key factor for the energy efficiency of biological brains. However, it is harder to train biologically-inspired spiking neural networks than artificial neural networks. This is puzzling given that theoretical results provide exact mapping algorithms from artificial to spiking neural networks with time-to-first-spike coding. In this paper we analyze in theory and simulation the learning dynamics of time-to-first-spike-networks and identify a specific instance of the vanishing-or-exploding gradient problem. While two choices of spiking neural network mappings solve this problem at initialization, only the one with a constant slope of the neuron membrane potential at threshold guarantees the equivalence of the training trajectory between spiking and artificial neural networks with rectified linear units. For specific image classification architectures comprising feed-forward dense or convolutional layers, we demonstrate that deep spiking neural network models can be effectively trained from scratch on MNIST and Fashion-MNIST datasets, or fine-tuned on large-scale datasets, such as CIFAR10, CIFAR100 and PLACES365, to achieve the exact same performance as that of artificial neural networks, surpassing previous spiking neural networks. Our approach accomplishes high-performance classification with less than 0.3 spikes per neuron, lending itself for an energy-efficient implementation. We also show that fine-tuning spiking neural networks with our robust gradient descent algorithm enables their optimization for hardware implementations with low latency and resilience to noise and quantization. To address challenges of training spiking neural networks (SNNs) at scale, the authors propose a scalable, approximation-free training method for deep SNNs using time-to-first-spike coding. They demonstrate enhanced performance and energy efficiency for neuromorphic hardware. [ABSTRACT FROM AUTHOR]

In this paper, we provide an overview of mitochondrial bioenergetics and specific conditions that lead to the formation of non-bilayer structures in mitochondria. Secondly, we provide a brief overview on the structure/function of cytotoxins and how snake venom cytotoxins have contributed to increasing our understanding of ATP synthesis via oxidative phosphorylation in mitochondria, to reconcile some controversial aspects of the chemiosmotic theory. Specifically, we provide an emphasis on the biochemical contribution of delocalized and localized proton movement, involving direct transport of protons though the Fo unit of ATP synthase or via the hydrophobic environment at the center of the inner mitochondrial membrane (proton circuit) on oxidative phosphorylation, and how this influences the rate of ATP synthesis. Importantly, we provide new insights on the molecular mechanisms through which cobra venom cytotoxins affect mitochondrial ATP synthesis, mitochondrial structure, and dynamics. Finally, we provide a perspective for the use of cytotoxins as novel pharmacological tools to study membrane bioenergetics and mitochondrial biology, how they can be used in translational research, and their potential therapeutic applications. [ABSTRACT FROM AUTHOR]

Spiking Neural Networks have gained significant attention due to their potential for energy efficiency and biological plausibility. However, the reduced number of user-friendly tools for designing, training, and visualizing Spiking Neural Networks hinders widespread adoption. This paper presents the SNNtrainer3D v1.0.0, a novel software application that addresses these challenges. The application provides an intuitive interface for designing Spiking Neural Networks architectures, with features such as dynamic architecture editing, allowing users to add, remove, and edit hidden layers in real-time. A key innovation is the integration of Three.js for three-dimensional visualization of the network structure, enabling users to inspect connections and weights and facilitating a deeper understanding of the model's behavior. The application supports training on the Modified National Institute of Standards and Technology dataset and allows the downloading of trained weights for further use. Moreover, it lays the groundwork for future integration with physical memristor technology, positioning it as a crucial tool for advancing neuromorphic computing research. The advantages of the development process, technology stack, and visualization are discussed. The SNNtrainer3D represents a significant step in making Spiking Neural Networks more accessible, understandable, and easier for Artificial Intelligence researchers and practitioners. [ABSTRACT FROM AUTHOR]

Air pollution poses a significant global health risk, with fine particulate matter (PM2.5) such as diesel exhaust particles (DEPs) being of particular concern due to their potential to drive systemic toxicities through bloodstream infiltration. The association between PM2.5 exposure and an increased prevalence of metabolic disorders, including obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM), is evident against a backdrop of rising global obesity and poor metabolic health. This paper examines the role of adipose tissue in mediating the effects of PM2.5 on metabolic health. Adipose tissue, beyond its energy storage function, is responsive to inhaled noxious stimuli, thus disrupting metabolic homeostasis and responding to particulate exposure with pro-inflammatory cytokine release, contributing to systemic inflammation. The purpose of this study was to characterize the metabolic response of adipose tissue in mice exposed to either DEPs or room air (RA), exploring both the adipokine profile and mitochondrial bioenergetics. In addition to a slight change in fat mass and a robust shift in adipocyte hypertrophy in the DEP-exposed animals, we found significant changes in adipose mitochondrial bioenergetics. Furthermore, the DEP-exposed animals had a significantly higher expression of adipose inflammatory markers compared with the adipose from RA-exposed mice. Despite the nearly exclusive focus on dietary factors in an effort to better understand metabolic health, these results highlight the novel role of environmental factors that may contribute to the growing global burden of poor metabolic health. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, for which current treatment options are limited. Recent studies have shed light on the role of mitochondria in ALS pathogenesis, making them an attractive therapeutic intervention target. This review contains a very comprehensive critical description of the involvement of mitochondria and mitochondria-mediated mechanisms in ALS. The review covers several key areas related to mitochondria in ALS, including impaired mitochondrial function, mitochondrial bioenergetics, reactive oxygen species, metabolic processes and energy metabolism, mitochondrial dynamics, turnover, autophagy and mitophagy, impaired mitochondrial transport, and apoptosis. This review also highlights preclinical and clinical studies that have investigated various mitochondria-targeted therapies for ALS treatment. These include strategies to improve mitochondrial function, such as the use of dichloroacetate, ketogenic and high-fat diets, acetyl-carnitine, and mitochondria-targeted antioxidants. Additionally, antiapoptotic agents, like the mPTP-targeting agents minocycline and rasagiline, are discussed. The paper aims to contribute to the identification of effective mitochondria-targeted therapies for ALS treatment by synthesizing the current understanding of the role of mitochondria in ALS pathogenesis and reviewing potential convergent therapeutic interventions. The complex interplay between mitochondria and the pathogenic mechanisms of ALS holds promise for the development of novel treatment strategies to combat this devastating disease. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations to the dystrophin gene, resulting in deficiency of dystrophin protein, loss of myofiber integrity in skeletal and cardiac muscle, and eventual cell death and replacement with fibrotic tissue. Pathologic cardiac manifestations occur in nearly every DMD patient, with the development of cardiomyopathy—the leading cause of death—inevitable by adulthood. As early cardiac abnormalities are difficult to detect, timely diagnosis and appropriate treatment modalities remain a challenge. There is no cure for DMD; treatment is aimed at delaying disease progression and alleviating symptoms. A comprehensive understanding of the pathophysiological mechanisms is crucial to the development of targeted treatments. While established hypotheses of underlying mechanisms include sarcolemmal weakening, upregulation of pro-inflammatory cytokines, and perturbed ion homeostasis, mitochondrial dysfunction is thought to be a potential key contributor. Several experimental compounds targeting the skeletal muscle pathology of DMD are in development, but the effects of such agents on cardiac function remain unclear. The synergistic integration of small molecule- and gene-target-based drugs with metabolic-, immune-, or ion balance-enhancing compounds into a combinatorial therapy offers potential for treating dystrophin deficiency-induced cardiomyopathy, making it crucial to understand the underlying mechanisms driving the disorder. [ABSTRACT FROM AUTHOR]

Mitochondria are essential for survival and as such, impairments in organelle homeostasis significantly accelerate age‐related morbidity and mortality. Here, we determined the contribution of bioenergetic efficiency to life span and health span in Drosophila melanogaster utilizing the mitochondrial uncoupler BAM15. Life span was determined in flies fed a normal diet (ND) or high fat diet (HFD) supplemented with vehicle or BAM15. Locomotor function was determined by negative geotaxis assay in middle‐aged flies fed vehicle or BAM15 under ND or HFD conditions. Redox capacity (high‐resolution respirometry/fluorometry), citrate synthase (enzyme activity), mtDNA content (qPCR), gene expression (qPCR), and protein expression (western blot) were assessed in flight muscle homogenates of middle‐aged flies fed vehicle or BAM15 ND. The molar ratio of H2O2 and O2 (H2O2:O2) in a defined respiratory state was calculated as a measure of redox balance. BAM15 extended life span by 9% on ND and 25% on HFD and improved locomotor activity by 125% on ND and 53% on HFD. Additionally, BAM15 enhanced oxidative phosphorylation capacity supported by pyruvate + malate, proline, and glycerol 3‐phosphate. Concurrently, BAM15 enhanced the mitochondrial H2O2 production rate, reverse electron flow from mitochondrial glycerol‐3‐phosphate dehydrogenase (mGPDH) to Complex I, mGPDH, and Complex I without altering the H2O2:O2 ratio. BAM15 upregulated transcriptional signatures associated with mitochondrial function and fitness as well as antioxidant defense. BAM15‐mediated restriction of bioenergetic efficiency prolongs life span and health span in Drosophila fed a ND or HFD. Improvements in life span and health span in ND were supported by synergistic enhancement of muscular redox capacity. [ABSTRACT FROM AUTHOR]

Sessile benthic organisms like oysters inhabit the intertidal zone, subject to alternating hypoxia and reoxygenation (H/R) episodes during tidal movements, impacting respiratory chain activities and metabolome compositions. We investigated the effects of constant severe hypoxia (90 min at ~ 0% O2) followed by 10 min reoxygenation, and cyclic hypoxia (5 cycles of 15 min at ~ 0% O2 and 10 min reoxygenation) on isolated mitochondria from the gill and the digestive gland of Crassostrea gigas respiring on pyruvate, palmitate, or succinate. Constant hypoxia suppressed oxidative phosphorylation (OXPHOS), particularly during Complex I-linked substrates oxidation. It had no effect on mitochondrial reactive oxygen species (ROS) efflux but increased fractional electron leak (FEL). In mitochondria oxidizing Complex I substrates, exposure to cyclic hypoxia prompted a significant drop after the first H/R cycle. In contrast, succinate-driven respiration only showed significant decline after the third to fifth H/R cycle. ROS efflux saw little change during cyclic hypoxia regardless of the oxidized substrate, but Complex I-driven FEL tended to increase with each subsequent H/R cycle. These observations suggest that succinate may serve as a beneficial stress fuel under H/R conditions, aiding in the post-hypoxic recovery of oysters by reducing oxidative stress and facilitating rapid ATP re-synthesis. The impacts of constant and cyclic hypoxia of similar duration on mitochondrial respiration and oxidative lesions in the proteins were comparable indicating that the mitochondrial damage is mostly determined by the lack of oxygen and mitochondrial depolarization. The ROS efflux in the mitochondria of oysters was minimally affected by oxygen fluctuations indicating that tight regulation of ROS production may contribute to robust mitochondrial phenotype of oysters and protect against H/R induced stress. [ABSTRACT FROM AUTHOR]

Background: Mitochondria are the 'powerhouses of cells' and progressive mitochondrial dysfunction is a hallmark of aging in skeletal muscle. Although different forms of exercise modality appear to be beneficial to attenuate aging-induced mitochondrial dysfunction, it presupposes that the individual has a requisite level of mobility. Moreover, non-exercise alternatives (i.e., nutraceuticals or pharmacological agents) to improve skeletal muscle bioenergetics require time to be effective in the target tissue and have another limitation in that they act systemically and not locally where needed. Mitochondrial transplantation represents a novel directed therapy designed to enhance energy production of tissues impacted by defective mitochondria. To date, no studies have used mitochondrial transplantation as an intervention to attenuate aging-induced skeletal muscle mitochondrial dysfunction. The purpose of this investigation, therefore, was to determine whether mitochondrial transplantation can enhance skeletal muscle bioenergetics in an aging rodent model. We hypothesized that mitochondrial transplantation would result in sustained skeletal muscle bioenergetics leading to improved functional capacity. Methods: Fifteen female mice (24 months old) were randomized into two groups (placebo or mitochondrial transplantation). Isolated mitochondria from a donor mouse of the same sex and age were transplanted into the hindlimb muscles of recipient mice (quadriceps femoris, tibialis anterior, and gastrocnemius complex). Results: The results indicated significant increases (ranging between ~36% and ~65%) in basal cytochrome c oxidase and citrate synthase activity as well as ATP levels in mice receiving mitochondrial transplantation relative to the placebo. Moreover, there were significant increases (approx. two-fold) in protein expression of mitochondrial markers in both glycolytic and oxidative muscles. These enhancements in the muscle translated to significant improvements in exercise tolerance. Conclusions: This study provides initial evidence showing how mitochondrial transplantation can promote skeletal muscle bioenergetics in an aging rodent model. [ABSTRACT FROM AUTHOR]

Time for post-exercise phosphocreatine-recovery (PCr-R), deemed a robust index of mitochondrial function in vivo, was previously reported to be elevated (signifying impaired ATP production) in veterans with Gulf War illness (GWI). Here we sought to replicate the finding and assess the impact of contravening previous eligibility requirements. The replication sample comprised white males. Cases reported ≥ moderate muscle-weakness to match the organ assessed to an organ affected; controls lacked recent headache or multiple symptoms. The expansion sample added cases without muscle-weakness, controls with recent headache, females, nonwhites. PCr-R, following pedal-depression-exercise, was compared in veterans with GWI versus controls (sample N = 38). In the replication sample, PCr-R results closely matched the prior report: PCr-R veterans with GWI mean(SD) = 47.7(16.5); control mean(SD) = 30.3(9.2), p = 0.017. (Prior-study PCr-R veterans with GWI mean(SD) = 46.1(17.9), control mean(SD) = 29.0(8.7), p = 0.023. Combined replication + prior samples: p = 0.001.) No case–control difference was observed in the expansion sample. In cases, PCr-R related to muscle-weakness: PCr-R = 29.9(7.1), 38.2(8.9), 47.8(15.2) for muscle-weakness rated none/low, intermediate, and high respectively (p for trend = 0.02), validating desirability of matching tissue assessed to tissue affected. In controls, headache/multiple symptoms, sex, and ethnicity each mattered (affecting PCr-R significantly). This study affirms mitochondrial/bioenergetic impairment in veterans with GWI. The importance of careful case/control selection is underscored. [ABSTRACT FROM AUTHOR]

Deep neural networks have achieved considerable success over the past ten years in a variety of fields. However, current state-of-the-art artificial intelligence (AI) systems require large computing hardware infrastructure and high power consumption. To overcome these hurdles, it is required to adopt new strategies such as designing novel computation architectures and developing building blocks that can mimic the low energy consumption of biological systems. On the architecture level, implementing classification tasks by splitting the problem into simpler subtasks is a way to relax hardware constraints despite the less accuracy of the approach. On the computation unit level, memristive devices are a promising technology for low power neuromorphic computation. Hereby, we combine both these two approaches and present a novel algorithmic approach for multiclass classification tasks through splitting the problem into binary subtasks while using optoelectronics memristors as synapses. Our approach leverages the core fundamentals from the One-vs-One (OvO) and the One-vs-Rest (OvR) classification strategies towards a novel Outcome-Driven One-vs-One (ODOvO) approach. The light modulation of synaptic weights, fed in our algorithm from experimental data, is a key enabling parameter that permits classification without modifying further applied electrical biases. Our approach requires at least a 10X less synapses (only 196 synapses are required) while reduces the classification time by up to N 2 compared to conventional memristors. We show that the novel ODOvO algorithm has similar accuracies to OvO (reaching over 60% on the MNIST dataset) while requiring even fewer iterations compared to the OvR. Consequently, our approach constitutes a feasible solution for neural networks where key priorities are the minimum energy consumption i.e., small iterations number, fast execution, and the low hardware requirements allowing experimental verification. [ABSTRACT FROM AUTHOR]

Determining how animals allocate energy, and how external factors influence this allocation, is crucial to understand species' life history requirements and response to disturbance. This response is driven in part by individuals' energy balance, prey characteristics, foraging behaviour and energy required for essential functions. We developed a bioenergetic model to estimate minimum foraging success rate (FSR), that is, the lowest possible prey capture rate for individuals to obtain the minimum energy intake needed to meet daily metabolic requirements, for female sperm whale (Physeter macrocephalus). The model was based on whales' theoretical energetic requirements using foraging and prey characteristics from animal‐borne tags and stomach contents, respectively. We used this model to simulate two prey structure change scenarios: (1) decrease in mean prey size, thus lower prey energy content and (2) decrease in prey size variability, reducing the variability in prey energy content. We estimate the whales need minimum of ~14% FSR to meet their energetic requirements, and energy intake is more sensitive to energy content changes than a decrease in energy variability. To estimate vulnerability to prey structure changes, we evaluated the compensation level required to meet bioenergetic demands. Considering a minimum 14% FSR, whales would need to increase energy intake by 21% (5–35%) and 49% (27–67%) to compensate for a 15% and 30% decrease in energy content, respectively. For a 30% and 50% decrease in energy variability, whales would need to increase energy intake by 13% (0–23%) and 24% (10–35%) to meet energetic demands, respectively. Our model demonstrates how foraging and prey characteristics can be used to estimate impact of changing prey structure in top predator energetics, which can help inform bottom‐up effects on marine ecosystems. We showed the importance of considering different FSR in bioenergetics models, as it can have decisive implications on estimates of energy acquired and affect the conclusions about top predator's vulnerability to possible environmental fluctuations. [ABSTRACT FROM AUTHOR]

Noise control, together with other regulatory functions facilitated by microRNAs (miRNAs), is believed to have played important roles in the evolution of multicellular eukaryotic organisms. miRNAs can dampen protein fluctuations via enhanced degradation of messenger RNA (mRNA), but this requires compensation by increased mRNA transcription to maintain the same expression levels. The overall mechanism is metabolically expensive, leading to questions about how it might have evolved in the first place. We develop a stochastic model of miRNA noise regulation, coupled with a detailed analysis of the associated metabolic costs. Additionally, we calculate binding free energies for a range of miRNA seeds, the short sequences which govern target recognition. We argue that natural selection may have fine-tuned the Michaelis-Menten constant KM describing miRNA-mRNA affinity and show supporting evidence from analysis of experimental data. KM is constrained by seed length, and optimal noise control (minimum protein variance at a given energy cost) is achievable for seeds of 6 to 7 nucleotides in length, the most commonly observed types. Moreover, at optimality, the degree of noise reduction approaches the theoretical bound set by the Wiener-Kolmogorov linear filter. The results illustrate how selective pressure toward energy efficiency has potentially shaped a crucial regulatory pathway in eukaryotes. [ABSTRACT FROM AUTHOR]

Background: Impaired brain bioenergetics is a pathological hallmark of Alzheimer's disease (AD) and is a compelling target for AD treatment. Patients with AD exhibit dysfunction in the brain creatine (Cr) system, which is integral in maintaining bioenergetic flux. Recent studies in AD mouse models suggest Cr supplementation improves brain mitochondrial function and may be protective of AD peptide pathology and cognition. Aims: The Creatine to Augment Bioenergetics in Alzheimer's disease (CABA) study is designed to primarily assess the feasibility of supplementation with 20 g/day of creatine monohydrate (CrM) in patients with cognitive impairment due to AD. Secondary aims are designed to generate preliminary data investigating changes in brain Cr levels, cognition, peripheral and brain mitochondrial function, and muscle strength and size. Methods: CABA is an 8-week, single-arm pilot study that will recruit 20 patients with cognitive impairment due to AD. Participants attend five in-person study visits: two visits at baseline to conduct screening and baseline assessments, a 4-week visit, and two 8-week visits. Outcomes assessment includes recruitment, retention, and compliance, cognitive testing, magnetic resonance spectroscopy of brain metabolites, platelet and lymphocyte mitochondrial function, and muscle strength and morphology at baseline and 8 weeks. Discussion: CABA is the first study to investigate CrM as a potential treatment in patients with AD. The pilot data generated by this study are pertinent to inform the design of future large-scale efficacy trials. Trial registration: ClinicalTrials.gov, NCT05383833, registered on 20 May 2022. [ABSTRACT FROM AUTHOR]

Euglena gracilis, a model organism of the eukaryotic supergroup Discoba harbouring also clinically important parasitic species, possesses diverse metabolic strategies and an atypical electron transport chain. While structures of the electron transport chain complexes and supercomplexes of most other eukaryotic clades have been reported, no similar structure is currently available for Discoba, limiting the understandings of its core metabolism and leaving a gap in the evolutionary tree of eukaryotic bioenergetics. Here, we report high-resolution cryo-EM structures of Euglena's respirasome I + III2 + IV and supercomplex III2 + IV2. A previously unreported fatty acid synthesis domain locates on the tip of complex I's peripheral arm, providing a clear picture of its atypical subunit composition identified previously. Individual complexes are re-arranged in the respirasome to adapt to the non-uniform membrane curvature of the discoidal cristae. Furthermore, Euglena's conformationally rigid complex I is deactivated by restricting ubiquinone's access to its substrate tunnel. Our findings provide structural insights for therapeutic developments against euglenozoan parasite infections. Euglena gracilis is a model organism of the eukaryotic supergroup Discoba, single-celled organisms containing mitochondria with discoid cristae. Here, the authors report structures of Euglena's transport chain supercomplex to reveal their distinctive architecture and working mechanisms. [ABSTRACT FROM AUTHOR]

The recovery of mitochondrial quality control (MQC) may bring innovative solutions for neuroprotection, while imposing a significant challenge given the need of holistic approaches to restore mitochondrial dynamics (fusion/fission) and turnover (mitophagy and biogenesis). In diabetic retinopathy, this is compounded by our lack of understanding of human retinal neurodegeneration, but also how MQC processes interact during disease progression. Here, we show that mitochondria hyperfusion is characteristic of retinal neurodegeneration in human and murine diabetes, blunting the homeostatic turnover of mitochondria and causing metabolic and neuro-inflammatory stress. By mimicking this mitochondrial remodelling in vitro, we ascertain that N6-furfuryladenosine enhances mitochondrial turnover and bioenergetics by relaxing hyperfusion in a controlled fashion. Oral administration of N6-furfuryladenosine enhances mitochondrial turnover in the diabetic mouse retina (Ins2Akita males), improving clinical correlates and conferring neuroprotection regardless of glycaemic status. Our findings provide translational insights for neuroprotection in the diabetic retina through the holistic recovery of MQC. Restoring mitochondrial function has emerged as a promising therapeutic strategy for diabetic retinopathy. Here, the authors show that mitochondrial hyperfusion blunts mitophagy during the disease process, and that rescuing this process pharmacologically confers retinal neuroprotection independent of an improved glycaemic status in type-1 diabetic mice. [ABSTRACT FROM AUTHOR]

Bioenergetics models estimate ectotherm growth, production, and prey consumption – all key for effective ecosystem management during changing global temperatures. Based on species‐specific allometric and thermodynamic relationships, these models typically use the species' lab‐derived optimum temperatures (physiological optimum) as opposed to empirical field data (realized thermal niche) that reflect actual thermal experience. Yet, dynamic behavioral thermoregulation mediated by biotic and abiotic interactions may provide substantial divergence between physiological optimum and realized thermal niche temperatures to significantly bias model outcomes. Here, using the Wisconsin bioenergetics model and in‐situ year‐round temperature data, we tested the two approaches and compared the maximum attainable lifetime weight and lifetime prey consumption estimates for two salmonid species with differing life histories. We demonstrate that using the realized thermal niche is the better approach because it eliminates significant biases in estimates produced by the physiological optimum. Specifically, using the physiological optimum, slower‐growing Salvelinus namaycush maximum attainable lifetime weight was underestimated, and consumption overestimated, while fast‐growing Oncorhynchus tshawytscha maximum attainable weight was overestimated. While the physiological optimum approach is useful for theoretical studies, our results demonstrate the critical importance that models used by management utilize up‐to‐date system‐ and species‐specific field data representing actual in‐situ behaviors (i.e., realized thermal niche). [ABSTRACT FROM AUTHOR]

Ten-Eleven-Translocase (TET) enzymes contribute to the regulation of the methylome via successive oxidation of 5-methyl cytosine (5mC) to derivatives which can be actively removed by base-excision-repair (BER) mechanisms in the absence of cell division. This is particularly important in post-mitotic neurons where changes in DNA methylation are known to associate with changes in neural function. TET3, specifically, is a critical regulator of both neuronal differentiation in development and mediates dynamic changes in the methylome of adult neurons associated with cognitive function. While DNA methylation is understood to regulate transcription, little is known of the specific targets of TET3-dependent catalytic activity in neurons. We report the results of an unbiased transcriptome analysis of the neuroblastoma-derived cell line; Neuro2A, in which Tet3 was silenced. Oxidative phosphorylation (OxPhos) was identified as the most significantly down-regulated functional canonical pathway, and these findings were confirmed by measurements of oxygen consumption rate in the Seahorse bioenergetics analyser. The mRNA levels of both nuclear- and mitochondrial-encoded OxPhos genes were reduced by Tet3-silencing, but we found no evidence for differential (hydroxy)methylation deposition at these gene loci. However, the mRNA expression of genes known to be involved in mitochondrial quality control were also shown to be significantly downregulated in the absence of TET3. One of these genes; EndoG, was identified as a direct target of TET3-catalytic activity at non-CpG methylated sites within its gene body. Accordingly, we propose that aberrant mitochondrial homeostasis may contribute to the decrease in OxPhos, observed upon Tet3-downregulation in Neuro2A cells. [ABSTRACT FROM AUTHOR]

After drawing comparisons between the reaction pathways of cytochrome c oxidase (CcO, Complex 4) and the preceding complex cytochrome bci (Complex 3), both being proton pumping complexes along the electron transport chain, we provide an analysis of the reaction pathways in bacterial ba3 class CcO, comparing spectroscopic results and kinetics observations with results from DFT calculations. For an important arc of the catalytic cycle in CcO, we can trace the energy pathways for the chemical protons and show how these pathways drive proton pumping of the vectorial protons. We then explore the proton loading network above the Fe heme a3-CuB catalytic center, showing how protons are loaded in and then released by combining DFT-based reaction energies with molecular dynamics simulations over states of that cycle. We also propose some additional reaction pathways for the chemical and vector protons based on our recent work with spectroscopic support. [ABSTRACT FROM AUTHOR]

In this paper, we provide an overview of mitochondrial bioenergetics and specific conditions that lead to the formation of non-bilayer structures in mitochondria. Secondly, we provide a brief overview on the structure/function of cytotoxins and how snake venom cytotoxins have contributed to increasing our understanding of ATP synthesis via oxidative phosphorylation in mitochondria, to reconcile some controversial aspects of the chemiosmotic theory. Specifically, we provide an emphasis on the biochemical contribution of delocalized and localized proton movement, involving direct transport of protons though the Fo unit of ATP synthase or via the hydrophobic environment at the center of the inner mitochondrial membrane (proton circuit) on oxidative phosphorylation, and how this influences the rate of ATP synthesis. Importantly, we provide new insights on the molecular mechanisms through which cobra venom cytotoxins affect mitochondrial ATP synthesis, mitochondrial structure, and dynamics. Finally, we provide a perspective for the use of cytotoxins as novel pharmacological tools to study membrane bioenergetics and mitochondrial biology, how they can be used in translational research, and their potential therapeutic applications.