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MBio Jul 2024an opportunistic fungal pathogen, produces the quorum-sensing molecule farnesol, which we have shown alters the transcriptional response and phenotype of human...
an opportunistic fungal pathogen, produces the quorum-sensing molecule farnesol, which we have shown alters the transcriptional response and phenotype of human monocyte-derived dendritic cells (DCs), including their cytokine secretion and ability to prime T cells. This is partially dependent on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ), which has numerous ligands, including the sphingolipid metabolite sphingosine 1-phosphate. Sphingolipids are a vital component of membranes that affect membrane protein arrangement and phagocytosis of by DCs. Thus, we quantified sphingolipid metabolites in monocytes differentiating into DCs by High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Farnesol increased the activity of serine palmitoyltransferase, leading to increased levels of 3-keto-dihydrosphingosine, dihydrosphingosine, and dihydrosphingosine 1-phosphate and inhibited dihydroceramide desaturase by inducing oxidative stress, leading to increased levels of dihydroceramide and dihydrosphingomyelin species and reduced ceramide levels. Accumulation of dihydroceramides can inhibit mitochondrial function; accordingly, farnesol reduced mitochondrial respiration. Dihydroceramide desaturase inhibition increases lipid droplet formation, which we observed in farnesol-treated cells, coupled with an increase in intracellular triacylglycerol species. Furthermore, inhibition of dihydroceramide desaturase with either farnesol or specific inhibitors impaired the ability of DCs to prime interferon-γ-producing T cells. The effect of farnesol on sphingolipid metabolism, triacylglycerol synthesis, and mitochondrial respiration was not dependent on PPAR-γ. In summary, our data reveal novel effects of farnesol on sphingolipid metabolism, neutral lipid synthesis, and mitochondrial function in DCs that affect their instruction of T cell cytokine secretion, indicating that can manipulate host cell metabolism via farnesol secretion.IMPORTANCE is a common commensal yeast, but it is also an opportunistic pathogen which is one of the leading causes of potentially lethal hospital-acquired infections. There is growing evidence that its overgrowth in the gut can influence diseases as diverse as alcohol-associated liver disease and COVID-19. Previously, we found that its quorum-sensing molecule, farnesol, alters the phenotype of dendritic cells differentiating from monocytes, impairing their ability to drive protective T cell responses. Here, we demonstrate that farnesol alters the metabolism of sphingolipids, important structural components of the membrane that also act as signaling molecules. In monocytes differentiating to dendritic cells, farnesol inhibited dihydroceramide desaturase, resulting in the accumulation of dihydroceramides and a reduction in ceramide levels. Farnesol impaired mitochondrial respiration, known to occur with an accumulation of dihydroceramides, and induced the accumulation of triacylglycerol and oil bodies. Inhibition of dihydroceramide desaturase resulted in the impaired ability of DCs to induce interferon-γ production by T cells. Thus, farnesol production by could manipulate the function of dendritic cells by altering the sphingolipidome.
PubMed: 38953353
DOI: 10.1128/mbio.00732-24 -
ELife Jul 2024We studied lysosomal Ca in inflammasome. Lipopolysaccharide (LPS) + palmitic acid (PA) decreased lysosomal Ca ([Ca]) and increased [Ca] through mitochondrial ROS, which...
We studied lysosomal Ca in inflammasome. Lipopolysaccharide (LPS) + palmitic acid (PA) decreased lysosomal Ca ([Ca]) and increased [Ca] through mitochondrial ROS, which was suppressed in -KO macrophages. Inflammasome activation and metabolic inflammation in adipose tissue of high-fat diet (HFD)-fed mice were ameliorated by KO. ER→lysosome Ca refilling occurred after lysosomal Ca release whose blockade attenuated LPS + PA-induced inflammasome. Subsequently, store-operated Caentry (SOCE) was activated whose inhibition suppressed inflammasome. SOCE was coupled with K efflux whose inhibition reduced ER Ca content ([Ca]) and impaired [Ca] recovery. LPS + PA activated KCa3.1 channel, a Ca-activated K channel. Inhibitors of KCa3.1 channel or KO reduced [Ca], attenuated increase of [Ca] or inflammasome activation by LPS + PA, and ameliorated HFD-induced inflammasome or metabolic inflammation. Lysosomal Ca release induced delayed JNK and ASC phosphorylation through CAMKII-ASK1. These results suggest a novel role of lysosomal Ca release sustained by ERlysosome Ca refilling and K efflux through KCa3.1 channel in inflammasome activation and metabolic inflammation.
Topics: Animals; Inflammasomes; Mice; Lysosomes; Calcium; Potassium; Inflammation; Mice, Knockout; Endoplasmic Reticulum; Lipopolysaccharides; TRPM Cation Channels; Intermediate-Conductance Calcium-Activated Potassium Channels; Mice, Inbred C57BL; Macrophages; Male; Diet, High-Fat
PubMed: 38953285
DOI: 10.7554/eLife.87561 -
PeerJ 2024Mitochondrial creatine kinase (MtCK) plays a pivotal role in cellular energy metabolism, exhibiting enhanced expression in various tumors, including colorectal cancer...
BACKGROUND
Mitochondrial creatine kinase (MtCK) plays a pivotal role in cellular energy metabolism, exhibiting enhanced expression in various tumors, including colorectal cancer (CRC). Creatine kinase mitochondrial 2 (CKMT2) is a subtype of MtCK; however, its clinical significance, biological functions, and underlying molecular mechanisms in CRC remain elusive.
METHODS
We employed immunohistochemical staining to discern the expression of CKMT2 in CRC and adjacent nontumor tissues of patients. The correlation between CKMT2 levels and clinical pathological factors was assessed. Additionally, we evaluated the association between CKMT2 and the prognosis of CRC patients using Kaplan-Meier survival curves and Cox regression analysis. Meanwhile, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression levels of in different CRC cell lines. Finally, we explored the biological functions and potential molecular mechanisms of CKMT2 in CRC cells through various techniques, including qRT-PCR, cell culture, cell transfection, western blot, Transwell chamber assays, flow cytometry, and co-immunoprecipitation.
RESULTS
We found that CKMT2 was significantly overexpressed in CRC tissues compared with adjacent nontumor tissues. The expression of CKMT2 is correlated with pathological types, tumor size, distant metastasis, and survival in CRC patients. Importantly, CKMT2 emerged as an independent prognostic factor through Cox regression analysis. Experimental downregulation of expression in CRC cell lines inhibited the migration and promoted apoptosis of these cells. Furthermore, we identified a novel role for CKMT2 in promoting aerobic glycolysis in CRC cells through interaction with lactate dehydrogenase B (LDHB).
CONCLUSION
In this study, we found the elevated expression of CKMT2 in CRC, and it was a robust prognostic indicator in CRC patients. CKMT2 regulates glucose metabolism amplifying the Warburg effect through interaction with LDHB, which promotes the growth and progression of CRC. These insights unveil a novel regulatory mechanism by which CKMT2 influences CRC and provide promising targets for future CRC therapeutic interventions.
Topics: Humans; Colorectal Neoplasms; Warburg Effect, Oncologic; Male; Female; Cell Line, Tumor; Prognosis; Creatine Kinase, Mitochondrial Form; Disease Progression; L-Lactate Dehydrogenase; Middle Aged; Cell Proliferation; Apoptosis; Gene Expression Regulation, Neoplastic
PubMed: 38952967
DOI: 10.7717/peerj.17672 -
Frontiers in Endocrinology 2024Ovarian aging is a complex process characterized by a decline in oocyte quantity and quality, directly impacting fertility and overall well-being. Recent researches have... (Review)
Review
Ovarian aging is a complex process characterized by a decline in oocyte quantity and quality, directly impacting fertility and overall well-being. Recent researches have identified mitochondria as pivotal players in the aging of ovaries, influencing various hallmarks and pathways governing this intricate process. In this review, we discuss the multifaceted role of mitochondria in determining ovarian fate, and outline the pivotal mechanisms through which mitochondria contribute to ovarian aging. Specifically, we emphasize the potential of targeting mitochondrial dysfunction through innovative therapeutic approaches, including antioxidants, metabolic improvement, biogenesis promotion, mitophagy enhancement, mitochondrial transfer, and traditional Chinese medicine. These strategies hold promise as effective means to mitigate age-related fertility decline and preserve ovarian health. Drawing insights from advanced researches in the field, this review provides a deeper understanding of the intricate interplay between mitochondrial function and ovarian aging, offering valuable perspectives for the development of novel therapeutic interventions aimed at preserving fertility and enhancing overall reproductive health.
Topics: Humans; Female; Mitochondria; Aging; Ovary; Animals; Antioxidants; Oocytes; Mitophagy
PubMed: 38952389
DOI: 10.3389/fendo.2024.1417007 -
Heliyon Jun 2024Uncoupling protein 2 (UCP2) is an ion/anion transporter in the mitochondrial inner membrane that plays a crucial role in immune response, regulation of oxidative stress,...
OBJECTIVE
Uncoupling protein 2 (UCP2) is an ion/anion transporter in the mitochondrial inner membrane that plays a crucial role in immune response, regulation of oxidative stress, and cellular metabolism. UCP2 polymorphisms are linked to chronic inflammation, obesity, diabetes, heart disease, exercise efficiency, and longevity. Daily step count and number of teeth are modifiable factors that reduce mortality risk, although the role of UCP2 in this mechanism is unknown. This study aimed to assess the possible effects of UCP2 polymorphisms on the association between daily step count and number of teeth with all-cause mortality.
METHODS
This study was conducted as a cohort project involving adult Japanese outpatients at Sado General Hospital (PROST). The final number of participants was 875 (mean age: 69 y). All-cause mortality during thirteen years (from June 2008 to August 2021) was recorded. The functional UCP2 genotypes rs659366 and rs660339 were identified using the Japonica Array®. Survival analyses were performed using multivariate Cox proportional hazard models.
RESULTS
There were 161 deaths (mean observation period: 113 months). Age, sex, daily step count, and the number of teeth were significantly associated with mortality. In females, UCP2 polymorphisms were associated with mortality independent of other factors (rs659366 GA compared to GG + AA; HR = 2.033, p = 0.019, rs660339 C T compared to CC + TT; HR = 1.911, p = 0.029). Multivariate models, with and without UCP2 genotypes, yielded similar results. The interaction terms between UCP2 genotype and daily step count or number of teeth were not significantly associated with mortality.
CONCLUSION
The effects of UCP2 polymorphisms on the association between daily step count or the number of teeth and all-cause mortality were not statistically significant. In females, UCP2 polymorphisms were significantly associated with all-cause mortality. Our findings confirmed the importance of physical activity and oral health and suggested a role of UCP2 in mortality risk independently with those factors.
PubMed: 38952382
DOI: 10.1016/j.heliyon.2024.e32512 -
Zhongguo Xue Xi Chong Bing Fang Zhi Za... Jun 2024To investigate the origin of in China, so as to provide insights into assessment of schistosomiasis mansoni transmission risk and control.
OBJECTIVE
To investigate the origin of in China, so as to provide insights into assessment of schistosomiasis mansoni transmission risk and control.
METHODS
Guanlan River, Dasha River, Shenzhen Reservoir, upper and lower reaches of Kuiyong River, and Xinzhen River in Shenzhen, China, were selected as sampling sites. Ten samples were collected from each site, and genomic DNA was extracted from samples. DNA samples were obtained from 15 sampled from 5 sampling sites in Minas Gerais State, Pará State, Federal District, Pernambuco State, and Sao Paulo State in Brazil, South America. Cytochrome c oxidase I () and mitochondrial 16S ribosomal RNA () genes were sampled using the above DNA templates, and the amplified products were sequenced. The and gene sequences were downloaded from GenBank, and the sampling sites were acquired. All and 1 gene sequences were aligned and evolutionary trees of were created based on and gene sequences to identify the genetic similarity and evolutionary relationship between samples from China and South America.
RESULTS
A total of 60 gene sequences with a length of 529 bp and 3 haplotypes were obtained from sampled from China. There were 165 gene sequences of retrieved from GenBank, and following alignment with the above 60 gene sequences, a total of 33 haplotypes were obtained. Phylogenetic analysis showed that the three haplotypes of from China were clustered into one clade, among which the haplotype China11 and three samples from Brazil retrieved from GenBank belonged to the same haplotype. Geographical evolution analysis showed that the samples from three sampling sites along eastern coasts of Brazil had the same haplotype with China11, and samples from other two sampling sites were closely, genetically related to China11. A total of 60 gene sequences with approximately 322 bp in length were amplified from in China, with 2 haplotypes identified. A total of 70 gene sequences of were captured from GenBank. Phylogenetic analysis showed that snails collected from China were clustered into a clade, and the haplotype China64 and the haplotype 229BS from Brazil shared the same haplotype. The 49 gene sequences of from 25 sampling sites in southern Brazil, which were captured from GenBank, were included in the present analysis, and the from 3 sampling sites shared the same haplotype with China64 in China. Geographical evolution analysis based on and gene sequences showed that sampled from eastern coastal areas of Brazil shared the same haplotypes in two gene fragment sequences with snails collected from China.
CONCLUSIONS
The snails in China are characterized as , which have a low genetic diversity. The snails in China have a high genetic similarity with sampled from eastern coastal areas of Brazil, which may have originated from the eastern coastal areas of Brazil.
Topics: Animals; China; Phylogeny; RNA, Ribosomal, 16S; Biomphalaria; Electron Transport Complex IV; Haplotypes
PubMed: 38952313
DOI: 10.16250/j.32.1374.2024069 -
Journal of Vascular Research Jun 2024The comorbidities of ischemic heart disease (IHD) and diabetes mellitus (DM) compromise the protection of the diabetic heart from ischemia/reperfusion (I/R) injury. We...
INTRODUCTION
The comorbidities of ischemic heart disease (IHD) and diabetes mellitus (DM) compromise the protection of the diabetic heart from ischemia/reperfusion (I/R) injury. We hypothesized that manipulation of reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways might protect the diabetic heart, and intervention of these pathways could be a new avenue for potentially protecting the diabetic heart.
METHODS
All hearts were subjected to 30-min ischemia and 30-min reperfusion. During reperfusion, hearts were exposed to molecules proven to protect the heart from I/R injury. The hemodynamic data were collected using suitable software. The infarct size, troponin T levels, and protein levels in hearts were evaluated.
RESULTS
Both cyclosporine-A and nitric oxide donor (SNAP) infusion at reperfusion protected 4-week diabetic hearts from I/R injury. However, 6-week diabetic hearts were protected only by SNAP, but not cyclosporin-A. These treatments significantly (p < 0.05) improved cardiac hemodynamics and decreased infarct size.
CONCLUSIONS
The administration of SNAP to diabetic hearts protected both 4- and 6-week diabetic hearts; however, cyclosporine-A protected only the 4-week diabetic hearts. The eNOS/GLUT-4 pathway executed the SNAP-mediated cardioprotection.
PubMed: 38952123
DOI: 10.1159/000539461 -
Cell Biochemistry and Function Jul 2024This review rigorously investigates the early cerebral changes associated with Alzheimer's disease, which manifest long before clinical symptoms arise. It presents... (Review)
Review
This review rigorously investigates the early cerebral changes associated with Alzheimer's disease, which manifest long before clinical symptoms arise. It presents evidence that the dysregulation of calcium (Ca) homeostasis, along with mitochondrial dysfunction and aberrant autophagic processes, may drive the disease's progression during its asymptomatic, preclinical stage. Understanding the intricate molecular interplay that unfolds during this critical period offers a window into identifying novel therapeutic targets, thereby advancing the treatment of neurodegenerative disorders. The review delves into both established and emerging insights into the molecular alterations precipitated by the disruption of Ca balance, setting the stage for cognitive decline and neurodegeneration.
Topics: Humans; Alzheimer Disease; Mitochondria; Calcium; Mitophagy; Autophagy; Animals; Hemostasis; Homeostasis
PubMed: 38951992
DOI: 10.1002/cbf.4085 -
Journal of Inherited Metabolic Disease Jul 2024Leucine aminoacyl tRNA-synthetase 1 (LARS1)-deficiency (infantile liver failure syndrome type 1 (ILFS1)) has a multisystemic phenotype including fever-associated acute...
Leucine aminoacyl tRNA-synthetase 1 (LARS1)-deficiency (infantile liver failure syndrome type 1 (ILFS1)) has a multisystemic phenotype including fever-associated acute liver failure (ALF), chronic neurologic abnormalities, and encephalopathic episodes. In order to better characterize encephalopathic episodes and MRI changes, 35 cranial MRIs from 13 individuals with LARS1 deficiency were systematically assessed and neurological phenotype was analyzed. All individuals had developmental delay and 10/13 had seizures. Encephalopathic episodes in 8/13 were typically associated with infections, presented with seizures and reduced consciousness, mostly accompanied by hepatic dysfunction, and recovery in 17/19 episodes. Encephalopathy without hepatic dysfunction occurred in one individual after liver transplantation. On MRI, 5/7 individuals with MRI during acute encephalopathy had deep gray matter and brainstem changes. Supratentorial cortex involvement (6/13) and cerebellar watershed injury (4/13) occurred with seizures and/or encephalopathy. Abnormal brainstem contour on sagittal images (8/13), atrophy (8/13), and myelination delay (8/13) were not clearly associated with encephalopathy. The pattern of deep gray matter and brainstem changes are apparently characteristic of encephalopathy in LARS1-deficiency, differing from patterns of hepatic encephalopathy or metabolic stroke in organic acidurias and mitochondrial diseases. While the pathomechanism remains unclear, fever and energy deficit during infections might be causative; thus, sufficient glucose and protein intake along with pro-active fever management is suggested. As severe episodes were observed during influenza infections, we strongly recommend seasonal vaccination.
PubMed: 38951950
DOI: 10.1002/jimd.12764 -
Journal of Nanobiotechnology Jul 2024Numerous studies have confirmed the involvement of extracellular vesicles (EVs) in various physiological processes, including cellular death and tissue damage. Recently,...
BACKGROUND
Numerous studies have confirmed the involvement of extracellular vesicles (EVs) in various physiological processes, including cellular death and tissue damage. Recently, we reported that EVs derived from ischemia-reperfusion heart exacerbate cardiac injury. However, the role of EVs from healthy heart tissue (heart-derived EVs, or cEVs) on myocardial ischemia-reperfusion (MI/R) injury remains unclear.
RESULTS
Here, we demonstrated that intramyocardial administration of cEVs significantly enhanced cardiac function and reduced cardiac damage in murine MI/R injury models. cEVs treatment effectively inhibited ferroptosis and maintained mitochondrial homeostasis in cardiomyocytes subjected to ischemia-reperfusion injury. Further results revealed that cEVs can transfer ATP5a1 into cardiomyocytes, thereby suppressing mitochondrial ROS production, alleviating mitochondrial damage, and inhibiting cardiomyocyte ferroptosis. Knockdown of ATP5a1 abolished the protective effects of cEVs. Furthermore, we found that the majority of cEVs are derived from cardiomyocytes, and ATP5a1 in cEVs primarily originates from cardiomyocytes of the healthy murine heart. Moreover, we demonstrated that adipose-derived stem cells (ADSC)-derived EVs with ATP5a1 overexpression showed much better efficacy on the therapy of MI/R injury compared to control ADSC-derived EVs.
CONCLUSIONS
These findings emphasized the protective role of cEVs in cardiac injury and highlighted the therapeutic potential of targeting ATP5a1 as an important approach for managing myocardial damage induced by MI/R injury.
Topics: Animals; Extracellular Vesicles; Mice; Myocardial Reperfusion Injury; Myocytes, Cardiac; Male; Mice, Inbred C57BL; Mitochondrial Proton-Translocating ATPases; Mitochondria; Myocardium; Reactive Oxygen Species; Ferroptosis; Disease Models, Animal
PubMed: 38951822
DOI: 10.1186/s12951-024-02618-x