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Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects

The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.

Urine electrooxidation for energy–saving hydrogen generation

Urea electrooxidation offers a cost-effective alternative to water oxidation for energy-saving hydrogen production. However, its practical application is limited by expensive urea reactants and sluggish reaction kinetics. Here, we present an efficient urine electrolysis system for hydrogen production, using cost-free urine as feedstock. Our system leverages a discovered Cl-mediated urea oxidation mechanism on Pt catalysts, where adsorbed Cl directly couple with urea to form N-chlorourea intermediates, which are then converted into N2 via intermolecular N–N coupling. This rapid mediated-oxidation process notably improves the activity and stability of urine electrolysis while avoiding Cl-induced corrosion, enabling over 200 hours of operation at reduced voltages. Accordingly, a notable reduction in the electricity consumption is achieved during urine electrolysis (4.05 kWh Nm−3) at 300 mA cm−2 in practical electrolyser for hydrogen production, outperforming the traditional urea (5.62 kWh Nm−3) and water (4.70–5.00 kWh Nm−3) electrolysis.

Synechococcus nitrogen gene loss in iron-limited ocean regions

Synechococcus are the most abundant cyanobacteria in high latitude regions and are responsible for an estimated 17% of annual marine net primary productivity. Despite their biogeochemical importance, Synechococcus populations have been unevenly sampled across the ocean, with most studies focused on low-latitude strains. In particular, the near absence of Synechococcus genomes from high-latitude, High Nutrient Low Chlorophyll (HNLC) regions leaves a gap in our knowledge of picocyanobacterial adaptations to iron limitation and their influence on carbon, nitrogen, and iron cycles. We examined Synechococcus populations from the subarctic North Pacific, a well-characterized HNLC region, with quantitative metagenomics. Assembly with short and long reads produced two near complete Synechococcus metagenome-assembled genomes (MAGs). Quantitative metagenome-derived abundances of these populations matched well with flow cytometry counts, and the Synechococcus MAGs were estimated to comprise >99% of the Synechococcus at Station P. Whereas the Station P Synechococcus MAGs contained multiple genes for adaptation to iron limitation, both genomes lacked genes for uptake and assimilation of nitrate and nitrite, suggesting a dependence on ammonium, urea, and other forms of recycled nitrogen leading to reduced iron requirements. A global analysis of Synechococcus nitrate reductase abundance in the TARA Oceans dataset found nitrate assimilation genes are also lower in other HNLC regions. We propose that nitrate and nitrite assimilation gene loss in Synechococcus may represent an adaptation to severe iron limitation in high-latitude regions where ammonium availability is higher. Our findings have implications for models that quantify the contribution of cyanobacteria to primary production and subsequent carbon export.

Archaean green-light environments drove the evolution of cyanobacteria’s light-harvesting system

Cyanobacteria induced the great oxidation event around 2.4 billion years ago, probably triggering the rise in aerobic biodiversity. While chlorophylls are universal pigments used by all phototrophic organisms, cyanobacteria use additional pigments called phycobilins for their light-harvesting antennas—phycobilisomes—to absorb light energy at complementary wavelengths to chlorophylls. Nonetheless, an enigma persists: why did cyanobacteria need phycobilisomes? Here, we demonstrate through numerical simulations that the underwater light spectrum during the Archaean era was probably predominantly green owing to oxidized Fe(III) precipitation. The green-light environments, probably shaped by photosynthetic organisms, may have directed their own photosynthetic evolution. Genetic engineering of extant cyanobacteria, simulating past natural selection, suggests that cyanobacteria that acquired a green-specialized phycobilin called phycoerythrobilin could have flourished under green-light environments. Phylogenetic analyses indicate that the common ancestor of modern cyanobacteria embraced all key components of phycobilisomes to establish an intricate energy transfer mechanism towards chlorophylls using green light and thus gained strong selective advantage under green-light conditions. Our findings highlight the co-evolutionary relationship between oxygenic phototrophs and light environments that defined the aquatic landscape of the Archaean Earth and envision the green colour as a sign of the distinct evolutionary stage of inhabited planets.

FpnA, the Aspergillus fumigatus homolog of human ferroportin, mediates resistance to nickel, cobalt and gallium but does not function in iron homeostasis

Iron homeostasis is key to both the survival of virtually all organisms and the virulence of fungi including Aspergillus fumigatus, a human fungal pathogen causing life-threatening invasive infections. Unlike the extensively studied fungal species Saccharomyces cerevisiae and Schizosaccharomyces pombe, A. fumigatus encodes an uncharacterized homolog of vertebrate ferroportin (Fpn1), termed FpnA. Fpn1 is the only known vertebrate iron efflux transporter, while microbial organisms are thought to lack iron efflux systems. After correcting the exon-intron annotation, inactivation and conditional overexpression of the A. fumigatus FpnA-encoding gene (fpnA) indicated, that FpnA mediates resistance to nickel, cobalt and gallium but not to iron, aluminium, cadmium, copper or zinc. Functional N-terminal tagging with a fluorescent protein demonstrated localization of FpnA in the vacuolar membrane, suggesting that FpnA detoxifies substrate metals by vacuolar deposition. In line, overexpression of fpnA reduced the utilization of urea as a nitrogen source, most likely by depriving cytosolic urease of its essential cofactor nickel. Phylogenetic analysis illustrated conservation of FpnA in all fungal divisions and several other eukaryotic lineages, underlining its crucial role in metal homeostasis. The divergent localization and functionalization of ferroportin homologs in two phylogenetic sister groups, metazoa and fungi, is of particular evolutionary interest.

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