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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.
Regulation of mammalian cellular metabolism by endogenous cyanide production
Small, gaseous molecules such as nitric oxide, carbon monoxide and hydrogen sulfide are produced as signalling molecules in mammalian cells. Here, we show that low concentrations of cyanide are generated endogenously in various mammalian tissues and cells. We detect cyanide in several cellular compartments of human cells and in various tissues and the blood of mice. Cyanide production is stimulated by glycine, occurs at the low pH of lysosomes and requires peroxidase activity. When generated at a specific rate, cyanide exerts stimulatory effects on mitochondrial bioenergetics, cell metabolism and cell proliferation, but impairs cellular bioenergetics at high concentrations. Cyanide can modify cysteine residues via protein S-cyanylation, which is detectable basally in cells and mice, and increases in response to glycine. Low-dose cyanide supplementation exhibits cytoprotective effects in hypoxia and reoxygenation models in vitro and in vivo. Conversely, pathologically elevated cyanide production in nonketotic hyperglycinaemia is detrimental to cells. Our findings indicate that cyanide should be considered part of the same group of endogenous mammalian regulatory gasotransmitters as nitric oxide, carbon monoxide and hydrogen sulfide.
Subcellular proteomics and iPSC modeling uncover reversible mechanisms of axonal pathology in Alzheimer’s disease
Dystrophic neurites (also termed axonal spheroids) are found around amyloid deposits in Alzheimer’s disease (AD), where they impair axonal electrical conduction, disrupt neural circuits and correlate with AD severity. Despite their importance, the mechanisms underlying spheroid formation remain incompletely understood. To address this, we developed a proximity labeling approach to uncover the proteome of spheroids in human postmortem and mouse brains. Additionally, we established a human induced pluripotent stem cell (iPSC)-derived AD model enabling mechanistic investigation and optical electrophysiology. These complementary approaches revealed the subcellular molecular architecture of spheroids and identified abnormalities in key biological processes, including protein turnover, cytoskeleton dynamics and lipid transport. Notably, the PI3K/AKT/mTOR pathway, which regulates these processes, was activated in spheroids. Furthermore, phosphorylated mTOR levels in spheroids correlated with AD severity in humans. Notably, mTOR inhibition in iPSC-derived neurons and mice ameliorated spheroid pathology. Altogether, our study provides a multidisciplinary toolkit for investigating mechanisms and therapeutic targets for axonal pathology in neurodegeneration.
Reprogramming of fatty acid metabolism: a hidden force regulating the occurrence and progression of cholangiocarcinoma
Cholangiocarcinoma (CCA) is a malignant tumor that originates from the bile duct epithelium and with a poor outcome due to lack of effective early diagnostic methods. Surgical resection is the preferred method for cure, but treatment options are limited for advanced diseases, such as distant metastatic or locally progressive tumors. Therefore, it is urgent to explore other new treatment methods. As modern living standards rise, the acceptance of high-fat, high-protein, and high-carbohydrate diets is growing among the public, and the resulting metabolic abnormalities are intimately linked to the initiation and spread of tumors. Metabolic reprogramming is a key mechanism in the process of tumor development and progression and is closely related to cancer cell proliferation, metastasis and drug resistance. Fatty acid (FA) metabolism, an integral component of cancer cell metabolism, can provide an energy source for cancer cells and participate in cell signaling, the regulation of the immune response and the maintenance of homeostasis of the internal environment, which are closely linked to the development and progression of CCA. Therefore, a better understanding of FA metabolism may provide promising strategies for early diagnosis, prognostic assessment and targeted therapy for CCA patients. In this paper, we review the effects of FA metabolism on CCA development and progression, summarize related mechanisms and the existing clinical applications of targeted lipid metabolism in CCA, and explore new targets for CCA metabolic therapy.
Demand-side strategies enable rapid and deep cuts in buildings and transport emissions to 2050
Decarbonization of energy-using sectors is essential for tackling climate change. We use an ensemble of global integrated assessment models to assess CO2 emissions reduction potentials in buildings and transport, accounting for system interactions. We focus on three intervention strategies with distinct emphases: reducing or changing activity, improving technological efficiency and electrifying energy end use. We find that these strategies can reduce emissions by 51–85% in buildings and 37–91% in transport by 2050 relative to a current policies scenario (ranges indicate model variability). Electrification has the largest potential for direct emissions reductions in both sectors. Interactions between the policies and measures that comprise the three strategies have a modest overall effect on mitigation potentials. However, combining different strategies is strongly beneficial from an energy system perspective as lower electricity demand reduces the need for costly supply-side investments and infrastructure.
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