In response to stress, mitochondrion undergoes constant morphological changes, including the formation of donut and spheroid mitochondria, and both are believed to be implicated in its biological functions.
Zeming Wu, Jie Ren, Guang-Hui Liu·31 Mar 2023
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In a recent study published in Cell Metabolism, Thomas A. Rando and colleagues reported a critical role of dysregulated glutathione (GSH) metabolism in driving the aging process of skeletal muscle stem cells (MuSCs), uncovering a novel mechanism underlying the divergent responses of quiescent stem cells to environmental stressors with age, thus providing a potentially accessible target to alleviate age-associated skeletal muscle degeneration.
Shiyu Liu and Jason W Locasale·24 May 2023
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Measurements of metabolic reactions under physiological conditions has been a challenging
problem. In a recent issue of Nature, Bartman et al. designed an isotope-labeling-based method to
measure tricarboxylic acid (TCA) fluxes in normal tissue and tumors in mice. The method revealed
that primary tumors exhibit lower TCA fluxes compared with normal tissue, consistent with
current knowledge. They also found that solid tumors generally exhibit lower energy production
rates.
Kevin C Klatt, Kevin Bass, John R Speakman, Kevin D Hall·26 Apr 2023
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Diet plays a substantial role in the etiology, progression, and treatment of chronic disease and is best considered as a multifaceted set of modifiable input variables with pleiotropic effects on a variety of biological pathways spanning multiple organ systems. This brief review discusses key issues related to the design and conduct of diet interventions in rodent models of metabolic disease and their implications for interpreting experiments. We also make specific recommendations to improve rodent diet studies to help better understand the role of diet on metabolic physiology and thereby improve our understanding of metabolic disease.
When glucose is replete, mTORC1 is active and anchored to the lysosomal surface via the two GTPases, RAG and Rheb, which are regulated by Ragulator and TSC2, respectively. When glucose is low, aldolase senses low fructose-1,6-bisphosphate and promotes the translocation of AXIN−LKB1 to the lysosomal surface, which leads to the activation of AMPK and the inhibition of RAGs, sundering mTORC1 from the lysosome and causing its inactivation. AMPK can also inactivate mTORC1 by phosphorylating Raptor and TSC2. However, the hierarchy of AXIN- and AMPK-mediated inhibition of mTORC1 remains poorly defined. Here, we show that AXIN translocation does not require AMPK expression or activity. In glucose starvation conditions, knockout of AXIN extended the half-life of mTORC1 inhibition from 15 min to 60 min, whereas knockout of AMPK only extended it to 30 min. RAGB GTP (constitutively active RAGB) almost entirely blocked the lysosomal dissociation and inhibition of mTORC1 under glucose starvation, but it did not inhibit AMPK, indicating that under these conditions it is AXIN lysosomal translocation that inhibits mTORC1, and it does so via inhibition of RAGs. AICAR, a mimetic of AMP, which activates both cytosolic AMPK and lysosomal AMPK, fully inhibited mTORC1 even when it is stably anchored to the lysosome by RAGB GTP, whereas glucose starvation mildly inhibited such anchored mTORC1. Together, we demonstrate that the lysosomal translocation of AXIN plays a primary role in glucose starvation-triggered inhibition of mTORC1 by inhibiting RAGs, and that AMPK activity inhibits mTORC1 through phosphorylating Raptor and TSC2, especially under severe stress.
The thermogenic brown and beige adipocytes consume fatty acids and generate heat to maintain core body temperature in the face of cold challenges. Since their validated presence in humans, the activation of thermogenic fat has been an attractive target for treating obesity and related metabolic diseases. Here, we reported that the opioid growth factor receptor (Ogfr) was highly expressed in adipocytes and promoted thermogenesis. The mice with genetic deletion of Ogfr in adipocytes displayed an impaired capacity to counter environmental cold challenges. Meanwhile, Ogfr ablation in adipocytes led to reduced fatty acid oxidation, enhanced lipid accumulation, impaired glucose tolerance, and exacerbated tissue inflammation under chronic high-fat diet (HFD)-fed conditions. At the cellular level, OGFr enhanced the production of mitochondrial trifunctional protein subunit α (MTPα) and also interacted with MTPα, thus promoting fatty acid oxidation. Together, our study demonstrated the important role of OGFr in fatty acid metabolism and adipose thermogenesis.
Yuzhou Gui, Ye Cao, Jiajin He, Chunyang Zhao, Wei Zheng, Ling Qian, Jie Cheng, Chengyin Yu, Chen Yu, Kun Lou, Gangyi Liu, Jingying Jia·10 May 2023
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The continuous emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants led to a rapid decline in protection efficacy and neutralizing titers even after three doses of COVID-19 vaccines. Here, we report an open-labeled phase I clinical trial of a modified mRNA vaccine (SYS6006) as a fourth-dose booster in healthy adults. Eighteen eligible participants, who had completed three doses of inactivated COVID-19 vaccines, received a fourth boosting dose of SYS6006-20 μg. Eighteen convalescent COVID-19 patients were enrolled for the collection of serum samples as a comparator of immunogenicity. The primary endpoint of this trial was titers of anti-receptor binding domain of spike glycoprotein (RBD) antibodies of the Omicron strain (BA.2 and BA.4/5) in serum; titers of neutralizing antibodies against pseudovirus of the Omicron strain (BA.2 and BA.4/5). The secondary endpoint was the incidence of adverse events within 30 days after the boosting. The exploratory endpoint was the cellular immune responses (interferon gamma, IFN-γ). This trial was registered with the Chinese Clinical Trial Registry (ChiCTR) website. No serious adverse events were reported within 30 days after vaccination. No grade 3 fever or serious adverse event was reported in the SYS6006 group. Notably, SYS6006 elicited higher titers and longer increases in anti-RBD antibodies and neutralizing antibodies (>90 days) compared with the convalescent group (P <0.0001) against Omicron strain (BA.2 and BA.4/5). Besides, higher positive spots of T-cell-secreting IFN-γ were observed in the SYS6006 group than those in the convalescent group (P <0.05). These data demonstrated that SYS6006 was well tolerated and highly immunogenic, generating a stronger and more durable immune response against different variants of SARS-CoV-2.
