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Physiological Reports Jun 2024Pancreatic β-cell mass is a critical determinant of insulin secretion. Severe endoplasmic reticulum (ER) stress causes β-cell apoptosis; however, the mechanisms of...
Pancreatic β-cell mass is a critical determinant of insulin secretion. Severe endoplasmic reticulum (ER) stress causes β-cell apoptosis; however, the mechanisms of progression and suppression are not yet fully understood. Here, we report that the autocrine/paracrine function of insulin reduces ER stress-induced β-cell apoptosis. Insulin reduced the ER-stress inducer tunicamycin- and thapsigargin-induced cell viability loss due to apoptosis in INS-1 β-cells. Moreover, the effect of insulin was greater than that of insulin-like growth factor-1 at physiologically relevant concentrations. Insulin did not attenuate the ER stress-induced increase in unfolded protein response genes. ER stress did not induce cytochrome c release from mitochondria. Mitochondrial hyperpolarization was induced by ER stress and prevented by insulin. The protonophore/mitochondrial oxidative phosphorylation uncoupler, but not the antioxidants N-acetylcysteine and α-tocopherol, exhibited potential cytoprotection during ER stress. Both procaspase-12 and cleaved caspase-12 levels increased under ER stress. The caspase-12 inhibitor Z-ATAD-FMK decreased ER stress-induced apoptosis. Caspase-12 overexpression reduced cell viability, which was diminished in the presence of insulin. Insulin decreased caspase-12 levels at the post-translational stages. These results demonstrate that insulin protects against ER stress-induced β-cell apoptosis in this cell line. Furthermore, mitochondrial hyperpolarization and increased caspase-12 levels are involved in ER stress-induced and insulin-suppressed β-cell apoptosis.
Topics: Insulin-Secreting Cells; Apoptosis; Endoplasmic Reticulum Stress; Animals; Insulin; Caspase 12; Rats; Mitochondria; Membrane Potential, Mitochondrial; Cell Survival
PubMed: 38884322
DOI: 10.14814/phy2.16106 -
Journal of Inflammation Research 2024Innate immunity is the first line of defense in the human body, and it plays an important role in defending against viral infection. Viruses are identified by different... (Review)
Review
Innate immunity is the first line of defense in the human body, and it plays an important role in defending against viral infection. Viruses are identified by different pattern-recognition receptors (PRRs) that activate the mitochondrial antiviral signaling protein (MAVS) or transmembrane protein 173 (STING), which trigger multiple signaling cascades that cause nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3) to produce inflammatory factors and interferons (IFNs). PRRs play a pivotal role as the first step in pathogen induction of interferon production. Interferon elicits antiviral activity by inducing the transcription of hundreds of IFN-stimulated genes (ISGs) via the janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway. An increasing number of studies have shown that environmental, pathogen and host factors regulate the IFN signaling pathway. Here, we summarize the mechanisms of host factor modulation in IFN production via pattern recognition receptors. These regulatory mechanisms maintain interferon levels in a normal state and clear viruses without inducing autoimmune disease.
PubMed: 38882189
DOI: 10.2147/JIR.S455035 -
Translational Cancer Research May 2024Proline dehydrogenase () encodes a mitochondrial protein that catalyzes the first step of proline degradation and is related to angiogenesis. Angiogenesis is a critical...
BACKGROUND
Proline dehydrogenase () encodes a mitochondrial protein that catalyzes the first step of proline degradation and is related to angiogenesis. Angiogenesis is a critical process in the development and progression of tumors, including lung adenocarcinoma (LUAD), as tumor growth and metastasis are dependent on angiogenesis. The mitochondria and their associated genes thus play a vital role in tumor therapy. However, the specific mechanism of action of in LUAD is not yet clear. The aim of this study was thus to clarify the specific mechanism of as a mitochondrial gene in LUAD.
METHODS
This study identified genes related to mitochondria and angiogenesis in LUAD. Based on the high and low expression of the genes in LUAD, we grouped them and conducted relevant bioinformatics analysis on the differentially expressed genes.
RESULTS
We screened genes related to mitochondria and angiogenesis in the differential genes of LUAD, and identified as a gene of interest. The expression of was associated with the survival outcome of patients with LUAD. Additionally, was found to be associated with immune cell infiltration and tumor mutations.
CONCLUSIONS
Mitochondrial metabolism and angiogenesis may have significant therapeutic ramifications for patients with LUAD. We identified , a gene exerts a dual role in cancer. PRODH may be a prospective therapeutic target in LUAD and a possible diagnostic and prognostic biomarker associated with immune infiltration and tumor mutational burden.
PubMed: 38881931
DOI: 10.21037/tcr-23-2109 -
PNAS Nexus Jun 2024Cardiomyocytes meet their high ATP demand almost exclusively by oxidative phosphorylation (OXPHOS). Adequate oxygen supply is an essential prerequisite to keep OXPHOS...
Cardiomyocytes meet their high ATP demand almost exclusively by oxidative phosphorylation (OXPHOS). Adequate oxygen supply is an essential prerequisite to keep OXPHOS operational. At least two spatially distinct mitochondrial subpopulations facilitate OXPHOS in cardiomyocytes, i.e. subsarcolemmal (SSM) and interfibrillar mitochondria (IFM). Their intracellular localization below the sarcolemma or buried deep between the sarcomeres suggests different oxygen availability. Here, we studied SSM and IFM isolated from piglet hearts and found significantly lower activities of electron transport chain enzymes and FF-ATP synthase in IFM, indicative for compromised energy metabolism. To test the contribution of oxygen availability to this outcome, we ventilated piglets under hyperbaric hyperoxic (HBO) conditions for 240 min. HBO treatment raised OXPHOS enzyme activities in IFM to the level of SSM. Complexome profiling analysis revealed that a high proportion of the FF-ATP synthase in the IFM was in a disassembled state prior to the HBO treatment. Upon increased oxygen availability, the enzyme was found to be largely assembled, which may account for the observed increase in OXPHOS complex activities. Although HBO also induced transcription of genes involved in mitochondrial biogenesis, a full proteome analysis revealed only minimal alterations, meaning that HBO-mediated tissue remodeling is an unlikely cause for the observed differences in OXPHOS. We conclude that a previously unrecognized oxygen-regulated mechanism endows cardiac OXPHOS with spatiotemporal plasticity that may underlie the enormous metabolic and contractile adaptability of the heart.
PubMed: 38881840
DOI: 10.1093/pnasnexus/pgae210 -
Journal of Experimental & Clinical... Jun 2024Cancer is characterized by dysregulated cellular metabolism. Thus, understanding the mechanisms underlying these metabolic alterations is important for developing...
BACKGROUND
Cancer is characterized by dysregulated cellular metabolism. Thus, understanding the mechanisms underlying these metabolic alterations is important for developing targeted therapies. In this study, we investigated the pro-tumoral effect of PDZ and LIM domain 2 (PDLIM2) downregulation in lung cancer growth and its association with the accumulation of mitochondrial ROS, oncometabolites and the activation of hypoxia-inducible factor-1 (HIF-1) α in the process.
METHODS
Databases and human cancer tissue samples were analyzed to investigate the roles of PDLIM2 and HIF-1α in cancer growth. DNA microarray and gene ontology enrichment analyses were performed to determine the cellular functions of PDLIM2. Seahorse assay, flow cytometric analysis, and confocal microscopic analysis were employed to study mitochondrial functions. Oncometabolites were analyzed using liquid chromatography-mass spectrometry (LC-MS). A Lewis lung carcinoma (LLC) mouse model was established to assess the in vivo function of PDLIM2 and HIF-1α.
RESULTS
The expression of PDLIM2 was downregulated in lung cancer, and this downregulation correlated with poor prognosis in patients. PDLIM2 highly regulated genes associated with mitochondrial functions. Mechanistically, PDLIM2 downregulation resulted in NF-κB activation, impaired expression of tricarboxylic acid (TCA) cycle genes particularly the succinate dehydrogenase (SDH) genes, and mitochondrial dysfunction. This disturbance contributed to the accumulation of succinate and other oncometabolites, as well as the buildup of mitochondrial reactive oxygen species (mtROS), leading to the activation of hypoxia-inducible factor 1α (HIF-1α). Furthermore, the expression of HIF-1α was increased in all stages of lung cancer. The expression of PDLIM2 and HIF-1α was reversely correlated in lung cancer patients. In the animal study, the orally administered HIF-1α inhibitor, PX-478, significantly reduces PDLIM2 knockdown-promoted tumor growth.
CONCLUSION
These findings shed light on the complex action of PDLIM2 on mitochondria and HIF-1α activities in lung cancer, emphasizing the role of HIF-1α in the tumor-promoting effect of PDLIM2 downregulation. Additionally, they provide new insights into a strategy for precise targeted treatment by suggesting that HIF-1α inhibitors may serve as therapy for lung cancer patients with PDLIM2 downregulation.
Topics: Humans; LIM Domain Proteins; Animals; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mitochondria; Reactive Oxygen Species; Down-Regulation; Lung Neoplasms; Cell Line, Tumor; Microfilament Proteins; Carcinoma, Lewis Lung; Gene Expression Regulation, Neoplastic; Female; Male
PubMed: 38880883
DOI: 10.1186/s13046-024-03094-9 -
Scientific Reports Jun 2024The Pama Croaker, Otolithoides pama, is an economically important fish species in Bangladesh. Intra-family similarities in morphology and typical barcode sequences of...
The Pama Croaker, Otolithoides pama, is an economically important fish species in Bangladesh. Intra-family similarities in morphology and typical barcode sequences of cox1 create ambiguities in its identification. Therefore, morphology and the complete mitochondrial genome of O. pama, and comparative mitogenomics within the family Sciaenidae have been studied. Extracted genomic DNA was subjected to Illumina-based short read sequencing for De-Novo mitogenome assembly. The complete mitogenome of O. pama (Accession: OQ784575.1) was 16,513 bp, with strong AC biasness and strand asymmetry. Relative synonymous codon usage (RSCU) among 13 protein-coding genes (PCGs) of O. pama was also analyzed. The studied mitogenomes including O. pama exhibited consistent sizes and gene orders, except for the genus Johnius which possessed notably longer mitogenomes with unique gene rearrangements. Different genetic distance metrics across 30 species of Sciaenidae family demonstrated 12S rRNA and the control region (CR) as the most conserved and variable regions, respectively, while most of the PCGs undergone a purifying selection. Different phylogenetic trees were congruent with one another, where O. pama was distinctly placed. This study would contribute to distinguishing closely related fish species of Sciaenidae family and can be instrumental in conserving the genetic diversity of O. pama.
Topics: Animals; Genome, Mitochondrial; Phylogeny; Perciformes; Codon Usage; Gene Order
PubMed: 38879694
DOI: 10.1038/s41598-024-64791-1 -
Diabetology & Metabolic Syndrome Jun 2024Interactions between multiple genes and environmental factors could be related to the pathogenesis of type 1 diabetes (T1D). The Brazilian population results from...
Interactions between multiple genes and environmental factors could be related to the pathogenesis of type 1 diabetes (T1D). The Brazilian population results from different historical miscegenation events, resulting in a highly diverse genetic pool. This study aimed to analyze the mtDNA of patients with T1D and to investigate whether there is a relationship between maternal ancestry, self-reported color and the presence of T1D. The mtDNA control region of 204 patients with T1D residing in three geographic regions of Brazil was sequenced following the International Society for Forensic Genetics (ISFG) recommendations. We obtained a frequency of Native American matrilineal origin (43.6%), African origin (38.2%), and European origin (18.1%). For self-declared color, 42.6% of the patients with diabetes reported that they were White, 50.9% were Brown, and 5.4% were Black. Finally, when we compared the self-declaration data with maternal ancestral origin, we found that for the self-declared White group, there was a greater percentage of haplogroups of Native American origin (50.6%); for the self-declared Black group, there was a greater percentage of African haplogroups (90.9%); and for the Brown group, there was a similar percentage of Native American and African haplogroups (42.3% and 45.2%, respectively). The Brazilian population with diabetic has a maternal heritage of more than 80% Native American and African origin, corroborating the country's colonization history.
PubMed: 38879575
DOI: 10.1186/s13098-024-01342-8 -
Biochimica Et Biophysica Acta.... Jun 2024A critical role for mitochondrial dysfunction has been shown in the pathogenesis of fibromyalgia. It is a chronic pain syndrome characterized by neuroinflammation and...
A critical role for mitochondrial dysfunction has been shown in the pathogenesis of fibromyalgia. It is a chronic pain syndrome characterized by neuroinflammation and impaired oxidative balance in the central nervous system. Boswellia serrata (BS), a natural polyphenol, is a well-known able to influence the mitochondrial metabolism. The objective of this study was to evaluate the mitochondrial dysfunction and biogenesis in fibromyalgia and their modulation by BS. To induce the model reserpine (1 mg/Kg) was subcutaneously administered for three consecutive days and BS (100 mg/Kg) was given orally for twenty-one days. BS reduced pain like behaviors in reserpine-injected rats and the astrocytes activation in the dorsal horn of the spinal cord and prefrontal cortex that are recognized as key regions associated with the neuropathic pain. Vulnerability to neuroinflammation and impaired neuronal plasticity have been described as consequences of mitochondrial dysfunction. BS administration increased PGC-1α expression in the nucleus of spinal cord and brain tissues, promoting the expression of regulatory genes for mitochondrial biogenesis (NRF-1, Tfam and UCP2) and cellular antioxidant defence mechanisms (catalase, SOD2 and Prdx 3). According with these data BS reduced lipid peroxidation and the GSSG/GSH ratio and increased SOD activity in the same tissues. Our results also showed that BS administration mitigates cytochrome-c leakage by promoting mitochondrial function and supported the movement of PGC-1α protein into the nucleus restoring the quality control of mitochondria. Additionally, BS reduced Drp1 and Fis1, preventing both mitochondrial fission and cell death, and increased the expression of Mfn2 protein, facilitating mitochondrial fusion. Overall, our results showed important mitochondrial dysfunction in central nervous system in fibromyalgia syndrome and the role of BS in restoring mitochondrial dynamics.
PubMed: 38878832
DOI: 10.1016/j.bbadis.2024.167301 -
Mitochondrial DNA. Part B, Resources 2024The complete mitochondrial genome of the (Ferrière, 1955) (Hymenoptera: Encyrtidae) was obtained through next-generation sequencing, making the first reported complete...
The complete mitochondrial genome of the (Ferrière, 1955) (Hymenoptera: Encyrtidae) was obtained through next-generation sequencing, making the first reported complete mitochondrial genome of the genus . The mitochondrial genome is 15,648 bp in length and includes 37 classical eukaryotic mitochondrial genes along with an A + T rich region. All 13 protein-coding genes (PCGs) initiate with typical ATN codons. Of these, 10 PCG genes terminate with TAA, while three terminate with TAG. Additionally, there are 22 tRNA genes, ranging in size from 62 to 70 bp. The maximum likelihood phylogenetic tree was constructed based on 13 PCGs, indicates that is closely related to . This mitochondrial genome will serve as a valuable molecular resource for species identification, genetic analysis, and comparative genomic studies of , contributing to the growing collection of mitochondrial genomes within the family Encyrtidae.
PubMed: 38873279
DOI: 10.1080/23802359.2024.2351539 -
Wellcome Open Research 2023We present a genome assembly from an individual male (the Notch-wing Button; Arthropoda; Insecta; Lepidoptera; Tortricidae). The genome sequence is 691.4 megabases in...
We present a genome assembly from an individual male (the Notch-wing Button; Arthropoda; Insecta; Lepidoptera; Tortricidae). The genome sequence is 691.4 megabases in span. Most of the assembly is scaffolded into 30 chromosomal pseudomolecules, including the Z sex chromosome. The mitochondrial genome has also been assembled and is 16.34 kilobases in length. Gene annotation of this assembly on Ensembl identified 21,886 protein coding genes.
PubMed: 38873190
DOI: 10.12688/wellcomeopenres.19843.1