Search Results (18)

The electrodynamics of current provide much of our technology, from telegraphs to the wired infrastructure powering the circuits of our electronic technology. Current flow is analyzed by its own rules that involve the Maxwell Ampere law and magnetism. Electrostatics does not involve magnetism, and so current flow and electrodynamics cannot be derived from electrostatics. Practical considerations also prevent current flow from being analyzed one charge at a time. There are too many charges, and far too many interactions to allow computation. Current flow is essential in biology. Currents are carried by electrons in mitochondria in an electron transport chain. Currents are carried by ions in nerve and muscle cells. Currents everywhere follow the rules of current flow: Kirchhoff’s current law and its generalizations. The importance of electron and proton flows in generating ATP was discovered long ago but they were not analyzed as electrical currents. The flow of protons and transport of electrons form circuits that must be analyzed by Kirchhoff’s law. A chemiosmotic theory that ignores the laws of current flow is incorrect physics. Circuit analysis is easily applied to short systems like mitochondria that have just one internal electrical potential in the form of the Hodgkin Huxley Katz (HHK) equation. The HHK equation combined with classical descriptions of chemical reactions forms a computable model of cytochrome c oxidase, part of the electron transport chain. The proton motive force is included as just one of the components of the total electrochemical potential. Circuit analysis includes its role just as it includes the role of any other ionic current. Current laws are now needed to analyze the flow of electrons and protons, as they generate ATP in mitochondria and chloroplasts. Chemiosmotic theory must be replaced by an electro-osmotic theory of ATP production that conforms to the Maxwell Ampere equation of electrodynamics while including proton movement and the proton motive force. Full article

Geological structures known as alkaline hydrothermal vents (AHVs) likely displayed dynamic energy characteristics analogous to cellular chemiosmosis and contained iron-oxyhydroxide green rusts in the early Earth. Under specific conditions, those minerals could have acted as non-enzymatic catalysts in the development of early bioenergetic chemiosmotic energy systems while being integrated into the membrane of AHV-produced organic vesicles. Here, we show that the simultaneous addition of two probable AHV components, namely nickel and amino acids, impacts green rust’s physico-chemical properties, especially those required for its incorporation in lipid vesicle’s membranes, such as decreasing the mineral size to the nanometer scale and increasing its hydrophobicity. These results suggest that such hydrophobic nano green rusts could fit into lipid vesicle membranes and could have functioned as a primitive, inorganic precursor to modern chemiosmotic metalloenzymes, facilitating both electron and proton transport in early life-like systems. Full article

Mitochondrial ATP synthesis is driven by harnessing the electrochemical gradient of protons (proton motive force) across the mitochondrial inner membrane via the process of chemiosmosis. While there is consensus that the proton gradient is generated by components of the electron transport chain, the mechanism by which protons are supplied to ATP synthase remains controversial. As opposed to a global coupling model whereby protons diffuse into the intermembrane space, a localised coupling model predicts that protons remain closely associated with the lipid membrane prior to interaction with ATP synthase. Herein, a revised version of the chemiosmotic theory is proposed by introducing an RNA-based proton sink which aligns the release of sequestered protons to availability of ADP and Pi thereby maximising the efficiency of oxidative phosphorylation. Full article

Circadian oscillations of several physiological and behavioral processes are an established process in all the organisms anticipating the geophysical changes recurring during the day. The time-keeping mechanism is controlled by a transcription translation feedback loop involving a set of well-characterized transcription factors. The synchronization of cells, controlled at the organismal level by a brain central clock, can be mimicked in vitro, pointing to the notion that all the cells are endowed with an autonomous time-keeping system. Metabolism undergoes circadian control, including the mitochondrial terminal catabolic pathways, culminating under aerobic conditions in the electron transfer to oxygen through the respiratory chain coupled to the ATP synthesis according to the oxidative phosphorylation chemiosmotic mechanism. In this study, we expanded upon previous isolated observations by utilizing multiple cell types, employing various synchronization protocols and different methodologies to measure mitochondrial oxygen consumption rates under conditions simulating various metabolic stressors. The results obtained clearly demonstrate that mitochondrial respiratory activity undergoes rhythmic oscillations in all tested cell types, regardless of their individual respiratory proficiency, indicating a phenomenon that can be generalized. However, notably, while primary cell types exhibited similar rhythmic respiratory profiles, cancer-derived cell lines displayed highly heterogeneous rhythmic changes. This observation confirms on the one hand the dysregulation of the circadian control of the oxidative metabolism observed in cancer, likely contributing to its development, and on the other hand underscores the necessity of personalized chronotherapy, which necessitates a detailed characterization of the cancer chronotype. Full article

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 F_o 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. Full article

Relative to several model bacteria, the ethanologenic bacterium Zymomonas mobilis is shown here to have elevated resistance to exogenous antimicrobial peptides (AMPs)— with regard to both peptide bulk concentration in the medium and the numbers of peptide molecules per cell. By monitoring the integration of AMPs in the bacterial cell membrane and observing the resulting effect on membrane energy coupling, it is concluded that the membranotropic effects of the tested AMPs in Z. mobilis and in Escherichia coli are comparable. The advantage of Z. mobilis over E. coli apparently results from its uncoupled mode of energy metabolism that, in contrast to E. coli, does not rely on oxidative phosphorylation, and hence, is less vulnerable to the disruption of its energy-coupling membrane by AMPs. It is concluded that the high resistance to antimicrobial peptides (AMPs) observed in Z. mobilis not only proves crucial for its survival in its natural environment but also offers a promising platform for AMP production and sheds light on potential strategies for novel resistance development in clinical settings. Full article

Humanity’s strive to understand why and how life appeared on planet Earth dates back to prehistoric times. At the beginning of the 19th century, empirical biology started to tackle this question yielding both Charles Darwin’s Theory of Evolution and the paradigm that the crucial trigger putting life on its tracks was the appearance of organic molecules. In parallel to these developments in the biological sciences, physics and physical chemistry saw the fundamental laws of thermodynamics being unraveled. Towards the end of the 19th century and during the first half of the 20th century, the tensions between thermodynamics and the “organic-molecules-paradigm” became increasingly difficult to ignore, culminating in Erwin Schrödinger’s 1944 formulation of a thermodynamics-compliant vision of life and, consequently, the prerequisites for its appearance. We will first review the major milestones over the last 200 years in the biological and the physical sciences, relevant to making sense of life and its origins and then discuss the more recent reappraisal of the relative importance of metal ions vs. organic molecules in performing the essential processes of a living cell. Based on this reassessment and the modern understanding of biological free energy conversion (aka bioenergetics), we consider that scenarios wherein life emerges from an abiotic chemiosmotic process are both thermodynamics-compliant and the most parsimonious proposed so far. Full article

Mitochondria have made a long evolutionary path from ancient bacteria immigrants within the eukaryotic cell to become key players for the cell, assuming crucial multitasking skills critical for human health and disease. Traditionally identified as the powerhouses of eukaryotic cells due to their central role in energy metabolism, these chemiosmotic machines that synthesize ATP are known as the only maternally inherited organelles with their own genome, where mutations can cause diseases, opening up the field of mitochondrial medicine. More recently, the omics era has highlighted mitochondria as biosynthetic and signaling organelles influencing the behaviors of cells and organisms, making mitochondria the most studied organelles in the biomedical sciences. In this review, we will especially focus on certain ‘novelties’ in mitochondrial biology “left in the shadows” because, although they have been discovered for some time, they are still not taken with due consideration. We will focus on certain particularities of these organelles, for example, those relating to their metabolism and energy efficiency. In particular, some of their functions that reflect the type of cell in which they reside will be critically discussed, for example, the role of some carriers that are strictly functional to the typical metabolism of the cell or to the tissue specialization. Furthermore, some diseases in whose pathogenesis, surprisingly, mitochondria are involved will be mentioned. Full article

The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that stimulate mitochondrial biogenesis to boost ATP production. Here, we examined the effects of deoxyribonucleosides (dNs) on mitochondrial biogenesis and function in Short chain enoyl-CoA hydratase 1 (ECHS1) ‘knockout’ (KO) cells, which exhibit combined defects in both oxidative phosphorylation (OXPHOS) and mitochondrial fatty acid β-oxidation (FAO). DNs treatment increased mitochondrial DNA (mtDNA) copy number and the expression of mtDNA-encoded transcripts in both CONTROL (CON) and ECHS1 KO cells. DNs treatment also altered global nuclear gene expression, with key gene sets including ‘respiratory electron transport’ and ‘formation of ATP by chemiosmotic coupling’ increased in both CON and ECHS1 KO cells. Genes involved in OXPHOS complex I biogenesis were also upregulated in both CON and ECHS1 KO cells following dNs treatment, with a corresponding increase in the steady-state levels of holocomplex I in ECHS1 KO cells. Steady-state levels of OXPHOS complex V, and the CIII₂/CIV and CI/CIII₂/CIV supercomplexes, were also increased by dNs treatment in ECHS1 KO cells. Importantly, treatment with dNs increased both basal and maximal mitochondrial oxygen consumption in ECHS1 KO cells when metabolizing either glucose or the fatty acid palmitoyl-L-carnitine. These findings highlight the ability of dNs to improve overall mitochondrial respiratory function, via the stimulation mitochondrial biogenesis, in the face of combined defects in OXPHOS and FAO due to ECHS1 deficiency. Full article

The emergence of complexity requires cooperation, yet selection typically favors defectors that do not cooperate. Such evolutionary conflict can be alleviated by a variety of mechanisms, allowing complexity to emerge. Chemiosmosis is one such mechanism. In syntrophic relationships, the chemiosmotic partner benefits simply from exporting products. Failure to do this can result in highly reduced electron carriers and detrimental amounts of reactive oxygen species. Nevertheless, the role of this mechanism in the history of life (e.g., the origin of eukaryotes from prokaryotes) seems questionable because of much lower atmospheric levels of oxygen and a largely anaerobic ocean. In this context, the role of sulfur should be considered. The last eukaryotic common ancestor (LECA) was a facultative aerobe. Under anaerobic conditions, LECA likely carried out various forms of anaerobic metabolism. For instance, malate dismutation, in which malate is both oxidized and reduced, allows re-oxidizing NADH. The terminal electron acceptor, fumarate, forms succinate when reduced. When oxygen is present, an excess of succinate can lead to reverse electron flow, forming high levels of reactive oxygen species. Under anaerobic conditions, reactive sulfur species may have formed. Eliminating end products may thus have had a selective advantage even under the low atmospheric oxygen levels of the Proterozoic eon. Full article

In the history of life, cooperation between biological units has led to increased complexity, e.g., eukaryotic cells and multicellular organisms. Cooperation requires limiting the gains of “defectors” in favor of the cooperative higher-level unit. Early in an evolutionary transition, bioenergetics and reactive oxygen species (ROS) may play a large role in managing these evolutionary conflicts. Chemiosmosis can be thought of as a poorly insulated wire—when supply exceeds demand, electrons are cast off and can form ROS. ROS signaling may thus lead to the dispersal of the excess products into the environment. These products may lead to groups and the formation of higher-level units that can subsequently be targeted by selection. Examining modern symbioses such as those between corals and photosynthetic dinoflagellates provides useful insight in this context. While ROS are an important factor in coral bleaching, little is known of the function of ROS under other circumstances, although some data suggest that ROS may modulate cooperation. ROS may have functioned similarly in the origin of eukaryotes, involving chemiosmotic mitochondria and chloroplasts. ROS may act as “arbiters” of evolutionary conflict, leading to cooperation via signaling pathways that favor the emergence of the higher-level unit. Full article

The existence of a K⁺ cycle in mitochondria has been predicted since the development of the chemiosmotic theory and has been shown to be crucial for several cellular phenomena, including regulation of mitochondrial volume and redox state. One of the pathways known to participate in K⁺ cycling is the ATP-sensitive K⁺ channel, MitoK_ATP. This channel was vastly studied for promoting protection against ischemia reperfusion when pharmacologically activated, although its molecular identity remained unknown for decades. The recent molecular characterization of MitoK_ATP has opened new possibilities for modulation of this channel as a mechanism to control cellular processes. Here, we discuss different strategies to control MitoK_ATP activity and consider how these could be used as tools to regulate metabolism and cellular events. Full article

Flight dispersal represents a key aspect of the evolutionary and ecological success of insects, allowing escape from predators, mating, and colonization of new niches. The huge energy demand posed by flight activity is essentially met by oxidative phosphorylation (OXPHOS) in flight muscle mitochondria. In insects, mitochondrial ATP supply and oxidant production are regulated by several factors, including the energy demand exerted by changes in adenylate balance. Indeed, adenylate directly regulates OXPHOS by targeting both chemiosmotic ATP production and the activities of specific mitochondrial enzymes. In several organisms, cytochrome c oxidase (COX) is regulated at transcriptional, post-translational, and allosteric levels, impacting mitochondrial energy metabolism, and redox balance. This review will present the concepts on how COX function contributes to flying insect biology, focusing on the existing examples in the literature where its structure and activity are regulated not only by physiological and environmental factors but also how changes in its activity impacts insect biology. We also performed in silico sequence analyses and determined the structure models of three COX subunits (IV, VIa, and VIc) from different insect species to compare with mammalian orthologs. We observed that the sequences and structure models of COXIV, COXVIa, and COXVIc were quite similar to their mammalian counterparts. Remarkably, specific substitutions to phosphomimetic amino acids at critical phosphorylation sites emerge as hallmarks on insect COX sequences, suggesting a new regulatory mechanism of COX activity. Therefore, by providing a physiological and bioenergetic framework of COX regulation in such metabolically extreme models, we hope to expand the knowledge of this critical enzyme complex and the potential consequences for insect dispersal. Full article

The evolution of the eukaryotic cell from the primal endosymbiotic event involved a complex series of adaptations driven primarily by energy optimization. Transfer of genes from endosymbiont to host and concomitant expansion (by infolding) of the endosymbiont’s chemiosmotic membrane greatly increased output of adenosine triphosphate (ATP) and placed selective pressure on the membrane at the host–endosymbiont interface to sustain the energy advantage. It is hypothesized that critical functions at this interface (metabolite exchange, polypeptide import, barrier integrity to proteins and DNA) were managed by a precursor β-barrel protein (“pβB”) from which the voltage-dependent anion-selective channel (VDAC) descended. VDAC’s role as hub for disparate and increasingly complex processes suggests an adaptability that likely springs from a feature inherited from pβB, retained because of important advantages conferred. It is proposed that this property is the remarkable structural flexibility evidenced in VDAC’s gating mechanism, a possible origin of which is discussed. Full article

Starting from the universal concept of entropy production, a large number of new results are obtained and a wealth of novel thermodynamic, kinetic, and molecular mechanistic insights are provided into the coupling of oxidation and ATP synthesis in the vital process of oxidative phosphorylation (OX PHOS). The total dissipation, $\Phi$ , in OX PHOS with succinate as respiratory substrate is quantified from measurements, and the partitioning of $\Phi$ into the elementary components of ATP synthesis, leak, slip, and other losses is evaluated for the first time. The thermodynamic efficiency, $\eta$ , of the coupled process is calculated from the data on $\Phi$ and shown to agree well with linear nonequilibrium thermodynamic calculations. Equations for the P/O ratio based on total oxygen consumed and extra oxygen consumed are derived from first principles and the source of basal (state 4) mitochondrial respiration is postulated from molecular mechanistic considerations based on Nath’s two-ion theory of energy coupling within the torsional mechanism of energy transduction and ATP synthesis. The degree of coupling, $q$ , between oxidation and ATP synthesis is determined from the experimental data and the irreversible thermodynamics analysis. The optimality of biological free energy converters is explored in considerable detail based on (i) the standard biothermodynamic approach, and (ii) a new biothermokinetic approach developed in this work, and an effective solution that is shown to arise from consideration of the molecular aspects in Nath’s theory is formulated. New experimental data in state 4 with uncouplers and redox inhibitors of OX PHOS and on respiratory control in the physiological state 3 with ADP and uncouplers are presented. These experimental observations are shown to be incompatible with Mitchell’s chemiosmotic theory. A novel scheme of coupling based on Nath’s two-ion theory of energy coupling within the torsional mechanism is proposed and shown to explain the data and also pass the test of consistency with the thermodynamics, taking us beyond the chemiosmotic theory. It is concluded that, twenty years since its first proposal, Nath’s torsional mechanism of energy transduction and ATP synthesis is now well poised to catalyze the progress of experimental and theoretical research in this interdisciplinary field. Full article