Mitochondria-related Genes Research Articles

Glucose-induced enhanced anti-oxidant activity inhibits apoptosis in goose fatty liver.

The development of mammalian nonalcoholic fatty liver disease is associated with oxidative stress, reduced mitochondrial function, and increased apoptosis in hepatocytes; however, the expressions of mitochondria-related genes are elevated in goose fatty liver, suggesting that there may be a unique protective mechanism in goose fatty liver. The aim of the study was to investigate this protective mechanism in terms of anti-oxidant capacity. Our data showed no substantial differences in the mRNA expression levels of the apoptosis-related genes including B-cell lymphoma-2 (Bcl-2), BCL2-associated X (Bax), cysteinyl aspartate-specific proteinase-3 (Caspase-3), and cysteinyl aspartate-specific proteinase-9 (Caspase-9) in the livers of the control and overfeeding Lander geese groups. The protein expression levels of Caspase-3 and cleaved Caspase-9 were not markedly different between the groups. Compared with the control group, malondialdehyde content was significantly lower (P < 0.01), glutathione peroxidase (GSH-Px) activity, glutathione (GSH) content, and mitochondrial membrane potential levels were higher (P < 0.01) in the overfeeding group. The mRNA expression levels of the anti-oxidant genes superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPX1), and glutathione peroxidase 2 (GPX2) were increased in goose primary hepatocytes after 40 mM and 60 mM glucose treatment. Reactive oxygen species (ROS) levels were significantly reduced (P < 0.01), whereas the mitochondrial membrane potential was maintained at normal levels. The mRNA expression levels of the apoptosis-related genes Bcl-2, Bax, and Caspase-3 were not substantial. There were no significant differences in the expression levels of Caspase-3 and cleaved Caspase-9 proteins. In conclusion, glucose-induced enhanced anti-oxidant capacity may help protect the function of mitochondria and inhibit the occurrence of apoptosis in goose fatty liver.

Second International Pulmonary Hypertension/Heart Failure Symposium—Structural heart disease, right ventricular dysfunction, and stem cell therapy: The European Pediatric Pulmonary Vascular Disease Network

Second International Pulmonary Hypertension/Heart Failure Symposium—Structural heart disease, right ventricular dysfunction, and stem cell therapy: The European Pediatric Pulmonary Vascular Disease Network

Low-Dose Radiation Reduces Doxorubicin-Induced Myocardial Injury Through Mitochondrial Pathways.

The use of doxorubicin (DOX) as an anthraquinone antineoplastic agent is limited due to its cardiotoxicity. Our previous study suggested that low-dose radiation (LDR) could mitigate the cardiotoxicity induced by DOX via suppressing oxidative stress and cell apoptosis. However, the molecular targets and protective mechanism of LDR are not understood. In the present study, we sought to investigate the mechanisms underlying LDR's cardioprotection. Balb/c mice were randomly divided into four groups: Control group (no treatment), DOX group, LDR group (75mGy), and LDR-72h-DOX group (LDR pretreatment followed by intraperitoneal injection of DOX). Electron microscopy, PCR, and Western blot analyses indicated that LDR pretreatment mitigated changes in mitochondrial morphology caused by DOX, upregulated activity of mitochondrial complexes, and restored ATP levels in cardiomyocytes that were decreased by DOX. Whole genome microarray and PCR analyses showed that mitochondrial-related genes were altered by LDR pretreatment. Thus, our study showed that LDR can protect cardiomyocytes against DOX through improving mitochondrial function and increasing ATP production. This research could inform DOX chemotherapy strategies and provide new insight into the molecule mechanisms underlying the cardioprotective effects of LDR.

Therapeutic Potential Targeting Podocyte Mitochondrial Dysfunction in Focal Segmental Glomerulosclerosis.

Podocytes are essential components of the glomerular filtration barrier and essential for the proper filtration function of the glomerulus. Podocyte injury under various stress conditions is the primary pathogenesis and key determinant of focal segmental glomerulosclerosis (FSGS) with prominent clinical manifestations of proteinuria or nephrotic syndrome. Under physiological conditions, a highly coordinated mitochondrial quality control system, including antioxidant defenses, mitochondrial dynamics (fusion, fission, and mitophagy), and mitochondrial biogenesis, guarantees the sophisticated structure and various functions of podocytes. However, under FSGS pathological conditions, mitochondria encounter oxidative stress, dynamics disturbances, and defective mitochondrial biogenesis. Moreover, mutations in mitochondrial DNA and mitochondria-related genes are also strongly associated with FSGS. Based on these pieces of evidence, bioactive agents that function to relieve mitochondrial oxidative stress and promote mitochondrial biogenesis have been proven effective in preclinical FSGS models. Targeting the mitochondrial network is expected to provide new therapeutic strategies for the treatment of FSGS and delay its progression to end-stage renal disease. Mitochondrial dysfunction plays a key role in podocyte injury and FSGS progression. This review summarized recent advances in the study of mitochondrial homeostatic imbalance and dysfunction in FSGS and discussed the potential of mitochondria-targeted therapeutics in improving FSGS and retarding its progression to end-stage renal disease.

Ginsenoside Rd Attenuates Lung Ischemia/Reperfusion Injury in Mice via Regulating Mitochondrial Function

In emergency and critical care medicine, lung ischemia-reperfusion injury is a prevalent disorder, which has significant morbidity and mortality. However, there is still a lack of effective means to block the lung ischemia-reperfusion injury. Established the lung ischemia-reperfusion injury model of mice; lung injury and histological analysis scoring were helpful to assess pathological injury in lung tissue; using an enzymelinked immunosorbent assay kit, expressed interleukin-6 and interleukin-1 in bronchoalveolar lavage fluids was determined. Seahorse analysis was used to examine the oxygen consumption rate and production of adenosine triphosphate. The expression of mitochondrial function-related genes was detected by realtime polymerase chain reaction; commercially available assay kits used for find the malondialdehyde production and catalase activity; apoptotic cells were detected using terminal deoxynucleotidyl transferase dUTP nick end labeling and protein expression was discovered using Western blotting. Ginsenoside alleviated the pathological changes caused by lung ischemia-reperfusion injury and reduced the lung injury score; ginsenoside Rd therapy reduced inflammatory cell infiltration significantly decreased lung bronchoalveolar lavage fluids interleukin-1 and interleukin-6 levels; ginsenoside Rd also increased the respiratory rate and the adenosine triphosphate production and regulated mitochondrial-related gene expression. Moreover, ginsenoside Rd ameliorated the lung ischemia-reperfusion injury-associated decrease in superoxide dismutase 2 expression, increase in malondialdehyde content and reduction in catalase activity. Additionally, ginsenoside Rd decreased lung ischemia-reperfusion injury-induced apoptosis. Ginsenoside Rd regulates the mitochondrial activity and thus protects against lung ischemiareperfusion injury.

Associations of Molecular-Genetic Bioenergetics and Chemotherapy-Induced Fatigue Symptoms in Patients with Breast Cancer: A proposal development

Introduction: Cancer-related fatigue (CRF) occurs in 82%-96% of cancer patients receiving chemotherapy (CT). CT-induced CRF is a distressing, persistent sense of exhaustion related to the disease or its treatment, and negatively impacts health outcomes. CRF is one of the most prevalent side effects of CT in patients with breast cancer. Despite various attempts to investigate the etiology of CRF, the biochemical mechanisms remain elusive. Objectives: The study aims to explore the molecular-genetic pathway of mitochondrial bioenergetics and its association with CT-induced CRF. We hypothesized that the chemotherapeutic agent containing anthracycline targets cell cycle progression, which triggers genetic and cellular instability, altering expression of mitochondrial genes and proteins, inducing reduced electron transport chain enzymatic activity and impaired oxidative phosphorylation, resulting in adenosine triphosphate (ATP) depletion and excessive reactive oxygen species (ROS) generation, leading to the development and intensification of CRF. Methods: This is a prospective, hypothesis-testing, and longitudinal study design. A total of 60 patients with breast cancer undergoing CT will be enrolled. Validated instruments will be used to measure CRF, depression, sleep disturbance, and physical activity. Whole blood sample will be collected before, during, and at the completion of CT to determine profiles of mitochondrial bioenergetics. A linear mixed model repeated measures analysis will be used to examine associations between changes in study variables. Anticipated Results: Increased scores of CRF will be associated with altered mitochondria-related genes and mitochondrial bioenergetics (e.g., ↓oxidative phosphorylation, ↓electron transport chain complexes activity, ↓ATP content, and ↑ROS production) in patients receiving CT-containing anthracyclines. Conclusion: The results will enable us to discover biomarkers, support the design of nonpharmacological interventions, and initiate precision symptom management to improve CRF.

Choroid plexus imaging to track neuroinflammation - a translational model for mouse and human studies.

Choroid plexus imaging to track neuroinflammation - a translational model for mouse and human studies.

Perfluorotetradecanoic Acid (PFTeDA) Induces Mitochondrial Damage and Oxidative Stress in Zebrafish (Danio rerio) Embryos/Larvae.

Industrial and consumer products, such as pesticides, lubricants, and cosmetics, can contain perfluorinated compounds (PFCs). Although many short-chain PFCs have been linked to physiological and behavioral changes in fish, there are limited data on longer-chain PFCs. The objective of this study was to determine the potential impact of perfluorotetradecanoic acid (PFTeDA) exposure on zebrafish (Danio rerio) during early developmental stages. We measured several endpoints including gene expression, mitochondrial bioenergetics, and locomotor activity in zebrafish. Survival, timing of hatching, and deformity frequency were unaffected by PFTeDA at the concentrations tested (0.01, 0.1, 1, and 10 µM) over a 7-day exposure period. The expression levels of mitochondrial-related genes (cox1 and mt-nd3) and oxidative stress-related genes (cat, hsp70, and hsp90a) were increased in larval fish with exposure to 10 µM PFTeDA; however, there was no change in oxidative respiration of embryos (i.e., basal respiration and oligomycin-induced ATP-linked respiration). Reactive oxygen species were reduced in larvae treated with 10 µM PFTeDA, coinciding with the increased transcription of antioxidant defense genes. Both the visual motor response test and light-dark preference test were conducted on 7 dpf larvae and yielded no significant findings. This study improves current knowledge regarding toxicity mechanisms for longer-chain PFCs such as PFTeDA.

Deciphering a mitochondria-related signature to supervise prognosis and immunotherapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major public health problem in humans. The imbalance of mitochondrial function has been discovered to be closely related to the development of cancer recently. However, the role of mitochondrial-related genes in HCC remains unclear. The RNA-sequencing profiles and patient information of 365 samples were derived from the Cancer Genome Atlas (TCGA) dataset. The mitochondria-related prognostic model was established by univariate Cox regression analysis and LASSO Cox regression analysis. We further determined the differences in immunity and drug sensitivity between low- and high-risk groups. Validation data were obtained from the International Cancer Genome Consortium (ICGC) dataset of patients with HCC. The protein and mRNA expression of six mitochondria-related genes in tissues and cell lines was verified by immunohistochemistry and qRT-PCR. The six mitochondria-related gene signature was constructed for better prognosis forecasting and immunity, based on which patients were divided into high-risk and low-risk groups. The ROC curve, nomogram, and calibration curve exhibited admirable clinical predictive performance of the model. The risk score was associated with clinicopathological characteristics and proved to be an independent prognostic factor in patients with HCC. The above results were verified in the ICGC validation cohort. Compared with normal tissues and cell lines, the protein and mRNA expression of six mitochondria-related genes was upregulated in HCC tissues and cell lines. The signature could be an independent factor that supervises the immunotherapy response of HCC patients and possess vital guidance value for clinical diagnosis and treatment.

Identification and validation of the mitochondrial function related hub genes by unsupervised machine learning and multi-omics analyses in lung adenocarcinoma

BackgroundThe mitochondrion and its associated genes were heavily implicated in developing and therapy tumors as the primary cellular organelle in charge of metabolic reprogramming and ferroptosis. Our work focuses on discovering new potential targets while analyzing the multi-omics data of mitochondria-related genes in lung adenocarcinoma (LUAD). MethodsThe Cancer Genome Atlas (TCGA) database provided multi-omics data for LUAD patients. Based on the expression profile of the genes associated with mitochondria, the patients were grouped by the unsupervised clustering method. R was used to explore the differential expressed protein-code gene, miRNA, and lncRNA, as well as their enriched functions and ceRNA networks. Additionally, the discrepancy between immune infiltration and genetic variation was comprehensively characterized. Our clinical samples and in vitro experiments investigated the hub gene determined by LASSO and batch analysis. ResultsTwo clusters are distinguished using unsupervised consensus clustering based on mitochondrial heterogeneity. The integrated analysis emphasized that patients in cluster B had a worse prognosis, higher mutation frequencies, and less immune cell infiltration. The hub genes DARS2 and COX5B are identified by further analysis using LASSO penalization. In vitro experiments indicated that DARS2 and COX5B knockdown inhibited tumor cell proliferation. The specimen of our hospital cohort conducted the immunohistochemistry analysis and validated that DARS2 and COX5B's expression was significantly higher in the tumor than in adjacent normal tissue and correlated to LUAD patients' prognosis. ConclusionOur observations implied that LUAD patients' tumors had distinct mitochondrial function heterogeneity with different clinical and molecular characteristics. DARS2 and COX5B might be critical genes involved in mitochondrial alterations and potential therapeutic targets.

A mitochondria-related signature for predicting immune microenvironment and therapeutic response in osteosarcoma.

Osteosarcoma remains to be the most devastating malignant tumor in children and teenagers. Mitochondria have also been proven to play critical roles in osteosarcoma. However, a mitochondria-related signature has been established in osteosarcoma to comprehensively evaluate the pathogenic roles and regulatory roles of mitochondria in osteosarcoma. In this study, osteosarcoma samples' transcriptome data and clinical information were collected from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) databases. A comprehensive bioinformatics analysis was performed on the samples at the bulk RNA sequencing level and single-cell RNA sequencing (scRNA-seq) level. EdU, Transwell, and immunohistochemistry (IHC) were performed on PCCB. A mitochondria-related signature was constructed in osteosarcoma patients. The prognostic value of the mitochondria-related signature was explored. The predictive value of the mitochondria-related signature in the immune microenvironment and chemotherapy agents was explored. The association between mitochondria and immunity in the tumor microenvironment of osteosarcoma at the scRNA-seq level was investigated. The tumorigenic role of the critical mitochondria-related gene, PCCB, was verified by in vitro validation. In conclusion, a mitochondria-related signature was developed in osteosarcoma with solid predictive values in the immune microenvironment, chemotherapy agents, and prognosis.

Acute Anemic Stress Is Modulated By Intercellular Mitochondria Transport from Erythroblastic Island Macrophages to Early Erythroblasts Via CD47-Sirpα Interactions

Stress erythropoiesis can be modulated by multiple cellular and molecular mediators from early stages of erythroblasts and precursors via cell intrinsic and extrinsic mechanisms. To investigate novel cell autonomous and non-autonomous mechanisms to overcome erythroid stress, we adopted phenylhydrazine (PHZ) induced acute anemic stress in mice and analyzed bulk RNA-seq on splenic early erythroblasts (Ter119+CD44high), and found significant enrichment of the early erythroid progenitor populations, as well as up-regulation of cell-cycle, DNA replication, proliferation and mitochondrial metabolism related genes (Gata1, Tal1, Sox6, E2Fs, Lin54, Foxo3 etc), suggesting that the most prominent erythroblastic cell-autonomous responses to stress include proliferation and energy metabolism. Next, we aim to explore the cell extrinsic pathways to mediate stress erythropoiesis from the perspective of the erythroid niche, i.e., erythroblastic islands (EBIs) macrophages. Intercellular mitochondria transfer is an emerging topic with implications in multiple biological processes, while it remains elusive whether mitochondria can be transported intercellularly within the EBIs, and if such a phenomenon is functionally relevant. In our study, we infused EBI macrophages into PHZ or serial bleeding induced anemic mice, and demonstrated that exogenous EBI macrophage infusion accelerated the erythroid regeneration in both modes of acute anemic stressors in a dynamic manner. More interestingly, we infused EBI macrophage isolated from mito-Dendra2 mice that express trackable mitochondria, and observed that mitochondria are transferred from EBI macrophages to early stages of erythroblasts. We conducted in vitro co-culture of EBI macrophages isolated from mito-Dendra2 mice and early erythroblasts isolated from PHZ treated tdTomato-Vav-Cre mice, and observed that mitochondria transfer mainly occurs via cell-cell contact mediated direct uptake during erythroid stress. Single cell RNA-sequencing (scRNA-seq) revealed that early erythroblasts receiving mitochondria exhibit up-regulation of a myriad of of proliferation signatures that are enriched in RNA binding (Rps2, Rpl28, Rpl10a, etc.), translation/protein synthesis (Eif5a, Eef1g, Ybx1, etc.), ATP metabolism (Atp5o, Atp5d, Atp6v0e, etc.) related molecular functions. The result pointed to the functional importance of intercellular mitochondria transfer to mediate the bioenergetic profiles of recipient erythroblasts by enhancing their protein/ATP synthesis and proliferation. Furthermore, scRNA-seq analysis revealed a subset of metabolically active erythroid populations marked by CD47 that receive higher abundance of mitochondria, as well as exhibiting enrichment in proliferation signatures, suggesting a potential role of the CD47 labelled erythroblasts in mitochondria transfer mediated erythroid regeneration. Notably, CD47 or Sirpα blockade in vivo leads to remarkable decline in both mitochondria transfer events as well as their mediated erythroid recovery. Thus, we postulate that there is a clear association between CD47 and mitochondria transfer mediated stress erythropoiesis. Collectively, our study explored the cell intrinsic and extrinsic pathways of early erythroblasts' responses to overcome stress, and shed light on the regulatory mechanisms of mitochondria transfer through CD47-SIRPα mediated cell-cell contacts and/or their downstream signaling in the context of stress erythropoiesis.

Research Progress on Mitochondrial Dysfunction in Diabetic Retinopathy

Diabetic Retinopathy (DR) is one of the most important microvascular complications of diabetes mellitus, which can lead to blindness in severe cases. Mitochondria are energy-producing organelles in eukaryotic cells, which participate in metabolism and signal transduction, and regulate cell growth, differentiation, aging, and death. Metabolic changes of retinal cells and epigenetic changes of mitochondria-related genes under high glucose can lead to mitochondrial dysfunction and induce mitochondrial pathway apoptosis. In addition, mitophagy and mitochondrial dynamics also change adaptively. These mechanisms may be related to the occurrence and progression of DR, and also provide valuable clues for the prevention and treatment of DR. This article reviews the mechanism of DR induced by mitochondrial dysfunction, and the prospects for related treatment.

Abstract 15325: Dynamic Change From Mitochondrial Compensation to Mitochondrial Failure During Aortic Disease Progression and Dissection Formation

Introduction: Ascending thoracic aortic aneurysm (ATAA) progression to dissection (ATAD) is associated with a high risk of mortality. Since the specific molecular and cellular changes leading to dissection are poorly understood, we compared transcriptome profiles of aortic smooth muscle cells (SMCs) between ATAD, ATAA, and controls. Methods: We performed single-cell RNA sequencing (scRNA-seq) of ascending aorta tissues from patients with acute ATAD (dissected and non-dissected areas were collected separately, 3 women, 5 men) and ATAA without dissection (3 women, 4 men), and from control subjects without aortic diseases (transplant donors, 3 women, 5 men). SMCs clusters were analyzed and immunofluorescence staining was performed to confirm expression of key genes. Mice exposed to β-aminopropionitrile monofumarate (BAPN) starting at P21 were used to investigate the changes of mitochondria-related genes during disease progression in undissected mice. Results: Compared with controls, SMCs in ATAA exhibited an adaptive response characterized by upregulation of a subset of focal adhesion and contractile genes and a pro-fibroblast phenotype. These expression changes were decreased in SMCs in ATAD, which instead exhibited significant increases in genes for inflammatory response, glycolysis, senescence and cell death. Additionally, mitochondrial genes including tricarboxylic acid (TCA) cycle genes (e.g. SDHB , FH , and MDH2 ) and mitochondria genome genes (e.g. MT-ND4 , MT-CO2 , and MT-CYB ), exhibited increased expression in ATAAs, and downregulated in ATADs. Immunofluorescence staining of corresponding proteins confirmed some key findings. Consistent with human data, scRNA-seq showed increased mitochondria-related genes in SMCs in BAPN mouse model at P35 when aneurysms form, which were decreased in the proximal aortic tissues after the onset of dissection deaths in surviving mice at P42. Conclusions: Our data suggest a dynamic change from mitochondrial compensation to failure with progression from normal to aortic aneurysms to dissections, which ultimately increases cell death pathways.

Collagen IV and Podocyte-Related Gene Variants in Patients with Concurrent IgA Nephropathy and Thin Basement Membrane Nephropathy

Introduction: IgA nephropathy is the most common primary glomerulonephritis among adults in clinic. Thin basement membrane nephropathy is often underestimated or even omitted if it coincides with IgA nephropathy. Therefore, it is necessary to study the epidemiological, clinical, and molecular characteristics of the concurrence of this entity. Methods: Eight patients with concurrent IgA nephropathy and thin basement membrane nephropathy (IgA-T) were retrospectively analyzed based on their clinicopathological characteristics. Genetic analysis was performed using whole-exome sequencing and Sanger’s sequencing. Data of the patients with IgA nephropathy and normal basement membrane (IgA-N) and variants in the local in-house database were used as controls. All candidate variants were assessed in silico. Results: The clinical manifestations of patients with IgA-T were hematuria, proteinuria, and renal insufficiency. Histopathological analysis showed mild mesangial hyperplasia, focal segmental glomerulosclerosis, podocyte activation, and foot process fusion. Crescent was rarely seen. COL4A and/or podocyte cytoskeleton and mitochondria-related gene variants were detected in seven IgA-T patients. Three patients exhibited pathogenic variants of COL4A, including a new variant. All IgA-T and one IgA-N patient possessed ITGB4 and/or PLEC variants, but there was no corresponding genotype-phenotype relationship. Six patients possessed other podocyte cytoskeleton and mitochondria-related gene variants such as NPHS2, SRGAP1, MYO1E, MYO1C, WT1, and COQ9, which were first reported in patients with IgA-T and were not in controls. Altogether, there were no significant differences in the degrees of proteinuria, serum creatinine, and eGFR during the follow-up period of 5–10 years, but there was a significant difference in the degree of proteinuria between IgA-T patients with podocyte-related gene variants and IgA-N patients. In the IgA-T group, patients with podocyte-related gene variants seemed predisposed to progress than patients without those variants, with higher proteinuria and serum creatinine and reduced eGFR. Conclusion: Concurrent thin basement membrane nephropathy and/or heterozygous COL4A gene pathogenic variants do not necessarily predict the short-term progress of sporadic IgA nephropathy in adults. Predisposition factors for this disease progression should be considered for detecting the variants of COL4A and podocyte cytoskeleton and mitochondria-related genes simultaneously, which also manifests the complexity and heterogeneity of IgA nephropathy with concurrent thin basement membrane nephropathy.

Abstract 13076: A Rare Stopgain Variant in SLC25A2 Associates With Low Nitric Oxide and Poor Clinical Outcome in Hypoplastic Left Heart Syndrome

Introduction: Mitochondrial respiration defects accompanied by low nitric oxide (NO) are associated with heart failure in congenital heart disease (CHD) patients with hypoplastic left heart syndrome (HLHS). Here we investigated the genetic etiology of low NO in patients with CHD. Hypothesis: Mutations in mitochondrial-related genes involved in NO metabolism contributes to the low NO associated risk for heart failure and need for heart transplantation in HLHS. Methods and Results: We performed a case-control association study among 588 white CHD cases including 41 with HLHS, and 24,143 white controls from the genome aggregation database (gnomAD). A rare conserved stopgain variant (rs562886845) in SLC25A2 encoding mitochondrial ornithine transporter was significantly enriched among the HLHS patients with poor clinical outcome (Group II, Table 1), with 15.8% carrying this mutation, yielding odds ratio of 17.07 ( p = 5.23 х 10 -4 ) in comparison to CHD patients without left ventricular outflow tract obstruction or 7.63 ( p =2.68 х 10 –3 ) in comparison to gnomAD control cohort. Significantly, SLC25A2 is the only mitochondrial transporter exporting asymmetric dimethylarginine, a natural NO synthase inhibitor. The three HLHS patients with this SLC25A2 variant showed very low nasal NO (nNO), a proxy for endogenous NO production capacity. All three patients had received heart transplant, with two being heterozygous and one homozygous for this variant. Significantly, the HLHS patient with the homozygous mutation had nNO at background levels (2.8 nl/min at 7 years of age as compared to &gt;200 nl/min expected nNO). Conclusions: Our findings uncovered an essential role for SLC25A2 in determining NO production capacity in patients with HLHS. As all three HLHS patients with this variant and very low nNO survived with heart transplant, this variant should be further investigated as a genetic marker for predicting the need for early heart transplant in HLHS.

A novel signature model based on mitochondrial-related genes for predicting survival of colon adenocarcinoma

BackgroundColon cancer is the foremost reason of cancer-related mortality worldwide. Colon adenocarcinoma constitutes 90% of colon cancer, and most patients with colon adenocarcinoma (COAD) are identified until advanced stage. With the emergence of an increasing number of novel pathogenic mechanisms and treatments, the role of mitochondria in the development of cancer, has been studied and reported with increasing frequency.MethodsWe systematically analyzed the effect of mitochondria-related genes in COAD utilizing RNA sequencing dataset from The Cancer Genome Atlas database and 1613 mitochondrial function-related genes from MitoMiner database. Our approach consisted of differentially expressed gene, gene set enrichment analysis, gene ontology terminology, Kyoto Encyclopedia of Genes and Genomes, independent prognostic analysis, univariate and multivariate analysis, Kaplan–Meier survival analysis, immune microenvironment correlation analysis, and Cox regression analysis.ResultsConsequently, 8 genes were identified to construct 8 mitochondrial-related gene model by applying Cox regression analysis, CDC25C, KCNJ11, NOL3, P4HA1, QSOX2, Trap1, DNAJC28, and ATCAY. Meanwhile, we assessed the connection between this model and clinical parameters or immune microenvironment. Risk score was an independent predictor for COAD patients’ survival with an AUC of 0.687, 0.752 and 0.762 at 1-, 3- and 5-year in nomogram, respectively. The group with the highest risk score had the lowest survival rate and the worst clinical stages. Additionally, its predictive capacity was validated in GSE39582 cohort.ConclusionIn summary, we established a prognostic pattern of mitochondrial-related genes, which can predict overall survival in COAD, which may enable a more optimized approach for the clinical treatment and scientific study of COAD. This gene signature model has the potential to improve prognosis and treatment for COAD patients in the future, and to be widely implemented in clinical settings. The utilization of this mitochondrial-related gene signature model may be benefit in the treatments and medical decision-making of COAD.

ß-tubulin contributes to Tongyang Huoxue decoction-induced protection against hypoxia/reoxygenation-induced injury of sinoatrial node cells through SIRT1-mediated regulation of mitochondrial quality surveillance

BackgroundTYHX-Tongyang Huoxue decoction has been used clinically for nearly 40 years. The ingredients of TYHX are Radix Astragali (Huangqi), Red Ginseng (Hongshen), Rehmannia Glutinosa (Dihuang), Common Yam Rhizome (Shanyao) and Cassia-bark-tree Bark (Rougui). Our previous experiments confirmed that TYHX can protect sinoatrial node cells. However, its mechanism of action is not completely understood yet. PurposeThe present study aimed to determine the protective effects of TYHX against Sinus node cell injury under hypoxic stress and elucidate the underlying mechanisms of protection. MethodsThrough RNA sequencing analysis and network pharmacology analysis, we found significant differences in mitochondrial-related genes before and after hypoxia-mimicking SNC, resolved the main regulatory mechanism of TYHX. Through the intervention of TYHX on SNC, a series of detection methods such as laser confocal, fluorescence co-localization, mitochondrial membrane potential and RT-PCR. The regulatory effect of TYHX on β-tubulin in sinoatrial node cells was verified by in vitro experiments. The mechanism of action of TYHX and its active ingredient quercetin to maintain mitochondrial homeostasis and protect sinoatrial node cells through mitophagy, mitochondrial fusion/fission and mitochondrial biosynthesis was confirmed. ResultsThrough RNA sequencing analysis, we found that there were significant differences in mitochondrial related genes before and after SNC was modeled by hypoxia. Through pharmacological experiments, we showed that TYHX could inhibit the migration of Drp1 to mitochondria, inhibit excessive mitochondrial fission, activate mitophagy and increase the mitochondrial membrane potential. These protective effects were mainly mediated by β-tubulin. Furthermore, the active component quercetin in TYHX could inhibit excessive mitochondrial fission through SIRT1, maintain mitochondrial energy metabolism and protect SNCs. Our results showed that protection of mitochondrial function through the maintenance of β-tubulin and activation of SIRT1 is the main mechanism by which TYHX alleviates hypoxic stress injury in SNCs. The regulatory effects of TYHX and quercetin on mitochondrial quality surveillance are also necessary. Our findings provide empirical evidence supporting the use of TYHX as a targeted treatment for sick sinus syndrome. ConclusionOur data indicate that TYHX exerts protective effects against sinus node cell injury under hypoxic stress, which may be associated with the regulation of mitochondrial quality surveillance (MQS) and inhibition of mitochondrial homeostasis-mediated apoptosis.

Alzheimer’s disease large-scale gene expression portrait identifies exercise as the top theoretical treatment

Alzheimer’s disease (AD) is a complex neurodegenerative disorder that affects multiple brain regions and is difficult to treat. In this study we used 22 AD large-scale gene expression datasets to identify a consistent underlying portrait of AD gene expression across multiple brain regions. Then we used the portrait as a platform for identifying treatments that could reverse AD dysregulated expression patterns. Enrichment of dysregulated AD genes included multiple processes, ranging from cell adhesion to CNS development. The three most dysregulated genes in the AD portrait were the inositol trisphosphate kinase, ITPKB (upregulated), the astrocyte specific intermediate filament protein, GFAP (upregulated), and the rho GTPase, RHOQ (upregulated). 41 of the top AD dysregulated genes were also identified in a recent human AD GWAS study, including PNOC, C4B, and BCL11A. 42 transcription factors were identified that were both dysregulated in AD and that in turn affect expression of other AD dysregulated genes. Male and female AD portraits were highly congruent. Out of over 250 treatments, three datasets for exercise or activity were identified as the top three theoretical treatments for AD via reversal of large-scale gene expression patterns. Exercise reversed expression patterns of hundreds of AD genes across multiple categories, including cytoskeleton, blood vessel development, mitochondrion, and interferon-stimulated related genes. Exercise also ranked as the best treatment across a majority of individual region-specific AD datasets and meta-analysis AD datasets. Fluoxetine also scored well and a theoretical combination of fluoxetine and exercise reversed 549 AD genes. Other positive treatments included curcumin. Comparisons of the AD portrait to a recent depression portrait revealed a high congruence of downregulated genes in both. Together, the AD portrait provides a new platform for understanding AD and identifying potential treatments for AD.

Mining the equine gut metagenome: poorly-characterized taxa associated with cardiovascular fitness in endurance athletes

Emerging evidence indicates that the gut microbiome contributes to endurance exercise performance. Still, the extent of its functional and metabolic potential remains unknown. Using elite endurance horses as a model system for exercise responsiveness, we built an integrated horse gut gene catalog comprising ~25 million unique genes and 372 metagenome-assembled genomes. This catalog represents 4179 genera spanning 95 phyla and functional capacities primed to exploit energy from dietary, microbial, and host resources. The holo-omics approach shows that gut microbiomes enriched in Lachnospiraceae taxa are negatively associated with cardiovascular capacity. Conversely, more complex and functionally diverse microbiomes are associated with higher glucose concentrations and reduced accumulation of long-chain acylcarnitines and non-esterified fatty acids in plasma, suggesting increased ß-oxidation capacity in the mitochondria. In line with this hypothesis, more fit athletes show upregulation of mitochondrial-related genes involved in energy metabolism, biogenesis, and Ca2+ cytosolic transport, all of which are necessary to improve aerobic work power, spare glycogen usage, and enhance cardiovascular capacity. The results identify an associative link between endurance performance and gut microbiome composition and gene function, laying the basis for nutritional interventions that could benefit horse athletes.