Mitochondrial epigenetics is rising as intriguing notion for its potential involvement in aging and diseases, while the details remain largely unexplored. Here it is shown that among the 13 mitochondrial DNA (mtDNA) encoded genes, NADH‐dehydrogenase 6 (ND6) transcript is primarily decreased in obese and type 2 diabetes populations, which negatively correlates with its distinctive hypermethylation. Hepatic mtDNA sequencing in mice unveils that ND6 presents the highest methylation level, which dramatically increases under diabetic condition due to enhanced mitochondrial translocation of DNA methyltransferase 1 (DNMT1) promoted by free fatty acid through adenosine 5’‐monophosphate (AMP)‐activated protein kinase (AMPK) activation. Hepatic knockdown of ND6 or overexpression of Dnmt1 similarly impairs mitochondrial function and induces systemic insulin resistance both in vivo and in vitro. Genetic or chemical targeting hepatic DNMT1 shows significant benefits against insulin resistance associated metabolic disorders. These findings highlight the pivotal role of ND6 epigenetic network in regulating mitochondrial function and onset of insulin resistance, shedding light on potential preventive and therapeutic strategies of insulin resistance and related metabolic disorders from a perspective of mitochondrial epigenetics.
Objective Cholesterol plays a pivotal role in mitochondrial steroidogenesis, membrane structure, and respiration. Mitochondrial membranes are intrinsically low in cholesterol content and therefore must be replenished with cholesterol from other subcellular membranes. However, the molecular mechanisms underlying mitochondrial cholesterol transport remains poorly understood. The Aster-B gene encodes a cholesterol binding protein recently implicated in cholesterol trafficking from the plasma membrane to the endoplasmic reticulum (ER). In this study, we investigated the function and underlying mechanism of Aster-B in mediating mitochondrial cholesterol transport. Methods CRISPR/Cas9 gene editing was carried out to generate cell lines deficient in Aster-B expression. The effect of Aster-B deficiency on mitochondrial cholesterol transport was examined by both confocal imaging analysis and biochemical assays. Deletion mutational analysis was also carried out to identify the function of a putative mitochondrial targeting sequence (MTS) at the N-terminus of Aster-B for its role in targeting Aster-B to mitochondria and in mediating mitochondrial cholesterol trafficking. Results Ablation of Aster-B impaired cholesterol transport from the ER to mitochondria, leading to a significant decrease in mitochondrial cholesterol content. Aster-B is also required for mitochondrial transport of fatty acids derived from hydrolysis of cholesterol esters. A putative MTS at the N-terminus of Aster-B mediates the mitochondrial cholesterol uptake. Deletion of the MTS or ablation of Arf1 GTPase which is required for mitochondrial translocation of ER proteins prevented mitochondrial cholesterol transport, leading to mitochondrial dysfunction. Conclusions We identified Aster-B as a key regulator of cholesterol transport from the ER to mitochondria. Aster-B also coordinates mitochondrial cholesterol trafficking with uptake of fatty acids derived from cholesterol esters, implicating the Aster-B protein as a novel regulator of steroidogenesis.
Punicalagin (PU) from pomegranate exerts beneficial effects on acute hyperlipidemia-induced hepatic abnormalities via regulation of oxidative stress and mitochondrial function.
Inflammation is a complex biological defense system associated with a series of chronic diseases such as cancer, arthritis, diabetes, cardiovascular and neurodegenerative diseases. The extracts of pomegranate fruit and peel have been reported to possess health-beneficial properties in inflammation-associated chronic diseases. Punicalagin is considered to be the major active component of pomegranate extracts. In this review we have focused on recent studies into the therapeutic effects of punicalagin on inflammation-associated chronic diseases and the regulatory roles in NF-κB, MAPK, IL-6/JAK/STAT3 and PI3K/Akt/mTOR signaling pathways. We have concluded that punicalagin may be a promising therapeutic compound in preventing and treating inflammation-associated chronic diseases, although further clinical studies are required.
Background: Safflower (Carthamus tinctorius L.) is a domesticated species with a long history of cultivation and widespread distribution across the globe, and light plays an important role in controlling its distribution boundary. Flowers from safflower have been widely used in traditional Chinese medicine because of their ability to improve cerebral blood flow. Flavonoids are the main active compounds in safflower and have many pharmacological effects. In this study, we aimed to explore the relationship between different light intensities and flavonoid biosynthesis in safflower flowers cultivated in greenhouse. Methods: The transcriptome of safflower flowers grown under different light intensities were sequenced through BGISEQ-500 platform. After assembled and filtered, Unigenes were annotated by aligning with seven functional databases. Differential expression analysis of two samples was performed with the DEseq2 package. Differentially expressed genes (DEGs) related with flavonoids biosynthesis were analyzed by Real-time PCR (RT-PCR). Flavonoids accumulation in flowers were determined by high performance liquid chromatography and spectrophotometer. Results: Transcriptome analysis of safflower flowers cultivated under different light intensities was performed. A total of 99.16 Gb data were obtained, and 78,179 Unigenes were annotated. Among the DEGs, 13 genes were related to flavonoid biosynthesis. The differential expressions of seven key genes were confirmed by RT-PCR. In addition, the levels of some flavonoids were measured in safflower flowers grown under different light intensities. CtHCT3 gene expression showed a significantly negative correlation with kaempferol content in safflower grown under different light intensities. Conclusion: Our results strongly suggested that the reduction in light intensity in a suitable range promoted flavonoid biosynthesis in safflower flowers. We suggest that the expressions of HCT genes played an important role in flavonoid accumulation in safflower flowers. Our study lays a foundation for further research on the effects of light on flavonoid biosynthesis in safflower.
Hyperlipidemia is associated with metabolic disorders, but the detailed mechanisms and related interventions remain largely unclear. As a functional food in Asian diets, Herba houttuyniae has been reported to have beneficial effects on health. The present research was to investigate the protective effects of Herba houttuyniae aqueous extract (HAE) on hyperlipidemia-induced liver and heart impairments and its potential mechanisms. Male C57BL/6J mice were administered with 200 or 400 mg/kg/day HAE for 9 days, followed by intraperitoneal injection with 0.5 g/kg poloxamer 407 to induce acute hyperlipidemia. HAE treatment significantly attenuated excessive serum lipids and tissue damage markers, prevented hepatic lipid deposition, improved cardiac remodeling, and ameliorated hepatic and cardiac oxidative stress induced by hyperlipidemia. More importantly, NF-E2 related factor (Nrf2)-mediated antioxidant and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)-mediated mitochondrial biogenesis pathways as well as mitochondrial complex activities were downregulated in the hyperlipidemic mouse livers and hearts, which may be attributable to the loss of adenosine monophosphate (AMP)-activated protein kinase (AMPK) activity: all of these changes were reversed by HAE supplementation. Our findings link the AMPK/PGC-1α/Nrf2 cascade to hyperlipidemia-induced liver and heart impairments and demonstrate the protective effect of HAE as an AMPK activator in the prevention of hyperlipidemia-related diseases.
Nutrient sensing by the mTOR complex 1 (mTORC1) requires its translocation to the lysosomal membrane. Upon amino acids removal, mTORC1 becomes cytosolic and inactive, yet its precise subcellular localization and the mechanism of inhibition remain elusive. Here, we identified Aster‐C as a negative regulator of mTORC1 signaling. Aster‐C earmarked a special rough ER subdomain where it sequestered mTOR together with the GATOR2 complex to prevent mTORC1 activation during nutrient starvation. Amino acids stimulated rapid disassociation of mTORC1 from Aster‐C concurrently with assembly of COP I vesicles which escorted mTORC1 to the lysosomal membrane. Consequently, ablation of Aster‐C led to spontaneous activation of mTORC1 and dissociation of TSC2 from lysosomes, whereas inhibition of COP I vesicle biogenesis or actin dynamics prevented mTORC1 activation. Together, these findings identified Aster‐C as a missing link between lysosomal trafficking and mTORC1 activation by revealing an unexpected role of COP I vesicles in mTORC1 signaling.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.