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In a recent series of papers, James W. Lee reported that mitochondrial oxidative phosphorylation violates the second law of thermodynamics and that it is allowed to do so because it is a "Type-B" process that features lateral and longitudinal membrane asymmetry. We show here that these contentions are based on problematic interpretations of the literature. More reliable values of ΔG_redox and ΔG_{ATP synthesis} show that the second law is not violated. More recent reports on the structures of the redox-driven proton pumps (Complexes I, III, and IV) suggest that longitudinal membrane asymmetry does not exist. Finally, Lee's predictions for the concentration of protons localized at the P-side surface of the bioenergetic membrane are likely to be much too high due to several errors; thus, his predicted high values of ΔpH_surface that violate the second law are likely to be wrong. There is currently no strong experimental or theoretical evidence to support the contention that oxidative phosphorylation violates the second law of thermodynamics. Show less

Ferroptosis, a form of regulated cell death mediated by lipid peroxidation (LPO), has become the subject of intense research due to its potential therapeutic applications in cancer chemotherapy as well as its pathophysiological role in ischemic organ injury. The role of mitochondrial lipid peroxidation (LPO) in ferroptosis remains poorly understood. We show that supplementation of exogenous iron in the form of ferric ammonium citrate (FAC) in combination with buthionine sulfoximine (BSO, an inhibitor of glutathione biosynthesis) induces mitochondrial lipid peroxidation that precedes ferroptosis in normal human fibroblasts. The mitochondrial-targeted antioxidant SkQ1 and the redox mediator methylene blue, which inhibits the production of reactive oxygen species (ROS) in complex I of the mitochondrial electron transport chain, prevent both mitochondrial lipid peroxidation and ferroptosis, but do not affect the cytosolic ROS accumulation. These data indicate that mitochondrial lipid peroxidation is required for ferroptosis induced by exogenous iron. FAC in the absence of BSO stimulates mitochondrial peroxidation without reducing cell viability. Glutathione depletion by BSO does not affect FAC-induced mitochondrial LPO but strongly stimulates the accumulation of ROS in the cytosol. These data allow us to conclude that mitochondrial LPO is not sufficient for ferroptosis and that cytosolic ROS mediates additional oxidative events that stimulate ferroptosis in conjunction with mitochondrial LPO. Show less

Lactic acidosis, a hallmark of solid tumour microenvironment, originates from lactate hyperproduction and its co-secretion with protons by cancer cells displaying the Warburg effect. Long considered a side effect of cancer metabolism, lactic acidosis is now known to play a major role in tumour physiology, aggressiveness and treatment efficiency. Growing evidence shows that it promotes cancer cell resistance to glucose deprivation, a common feature of tumours. Here we review the current understanding of how extracellular lactate and acidosis, acting as a combination of enzymatic inhibitors, signal, and nutrient, switch cancer cell metabolism from the Warburg effect to an oxidative metabolic phenotype, which allows cancer cells to withstand glucose deprivation, and makes lactic acidosis a promising anticancer target. We also discuss how the evidence about lactic acidosis' effect could be integrated in the understanding of the whole-tumour metabolism and what perspectives it opens up for future research. Show less

Aerobic energy metabolism is driven by proton-pumping respiratory supercomplexes. The study reports the structural basis for energy conversion in such supercomplex. It may aid metabolic engineering and drug design against diphtheria and tuberculosis. Show less

Cryo-electron microscopy studies of Escherichia coli complex I suggest a conserved mechanism of coupled proton transfers and electrostatic interactions that result in proton ejection from the complex exclusively at the distal NuoL subunit. Show less

The nuclear factor-erythroid 2 p45-related factor 2 (NRF2, also called Nfe2l2) and its cytoplasmic repressor, Kelch-like ECH-associated protein 1 (KEAP1), are major regulators of redox homeostasis controlling a multiple of genes for detoxification and cytoprotective enzymes. The NRF2/KEAP1 pathway is a fundamental signaling cascade responsible for the resistance of metabolic, oxidative stress, inflammation, and anticancer effects. Interestingly, a recent accumulation of evidence has indicated that NRF2 exhibits an aberrant activation in cancer. Evidence has shown that the NRF2/KEAP1 signaling pathway is associated with the proliferation of cancer cells and tumerigenesis through metabolic reprogramming. In this review, we provide an overview of the regulatory molecular mechanism of the NRF2/KEAP1 pathway against metabolic reprogramming in cancer, suggesting that the regulation of NRF2/KEAP1 axis might approach as a novel therapeutic strategy for cancers. Show less

For decades, microbiologists have viewed the acetyl CoA pathway and organisms that use it for H₂-dependent carbon and energy metabolism, acetogens and methanogens, as ancient. Classical evidence and newer evidence indicating the antiquity of the acetyl CoA pathway are summarized here. The acetyl CoA pathway requires approximately 10 enzymes, roughly as many organic cofactors, and more than 500 kDa of combined subunit molecular mass to catalyze the conversion of H₂ and CO₂ to formate, acetate, and pyruvate in acetogens and methanogens. However, a single hydrothermal vent alloy, awaruite (Ni₃Fe), can convert H₂ and CO₂ to formate, acetate, and pyruvate under mild hydrothermal conditions on its own. The chemical reactions of H₂ and CO₂ to pyruvate thus have a natural tendency to occur without enzymes, given suitable inorganic catalysts. This suggests that the evolution of the enzymatic acetyl CoA pathway was preceded by-and patterned along-a route of naturally occurring exergonic reactions catalyzed by transition metal minerals that could activate H₂ and CO₂ by chemisorption. The principle of forward (autotrophic) pathway evolution from preexisting non-enzymatic reactions is generalized to the concept of patterned evolution of pathways. In acetogens, exergonic reduction of CO₂ by H₂ generates acyl phosphates by highly reactive carbonyl groups undergoing attack by inert inorganic phosphate. In that ancient reaction of biochemical energy conservation, the energy behind formation of the acyl phosphate bond resides in the carbonyl, not in phosphate. The antiquity of the acetyl CoA pathway is usually seen in light of CO₂ fixation; its role in primordial energy coupling via acyl phosphates and substrate-level phosphorylation is emphasized here. Show less