Specific effects of nalidixic acid on mitochondrial gene expression in Saccharomyces cerevisiae.
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Anti-Bacterial Agents↗
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Results for “mitochondrial gene expression”
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Mitochondrial dysfunction fuels drug resistance in adult T-cell acute lymphoblastic leukemia.
BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is a relatively rare hematological malignancy, characterized by the uncontrolled proliferation of immature T lymphoblasts and associated with a generally unfavorable prognosis. Our previous research has demonstrated that decreased mitochondrial activity is associated with the aggressiveness of T-ALL tumors. However, the mechanisms underlying this phenomenon and its contribution to treatment resistance remain largely elusive. METHODS: We have built up the largest known T-ALL tumor bank, with a median follow-up of 32 months, including our transcriptomic data from 79 newly sequenced tumors that adds to the 54 publicly accessible samples. Computational analyses and a series of functional assays were performed to investigate the molecular links between altered mitochondrial activity and drug resistance. RESULTS: The transcriptomic analysis revealed that down-regulation of mitochondrial activity is a potent driver of ABCB1 activation, a gene strongly associated with multidrug resistance. In tumors with low mitochondrial activity, the impaired fatty acids β-oxidation leads to intracellular lipid accumulation, which is directly involved in ABCB1 activation. Indeed, our data show that lipid neo-synthesis and accumulation promotes the activation of lipogenic transcription factors, liver X receptors (LXRs), which act as drivers of ABCB1 expression. Tumor data analyses confirmed that high ABCB1 expression in tumour samples is indeed associated with reduced mitochondrial gene expression, lipid droplet enrichment, increased tumour aggressiveness, and significantly shorter patient survival. CONCLUSIONS: Our study demonstrates that reduced mitochondrial activity drives multidrug resistance in adult T-ALL via lipid-mediated activation of ABCB1. These findings enhance our understanding of the biology of aggressive T-ALL and provide insight into mechanisms of resistance to conventional chemotherapy. Consequently, we propose that targeting de novo lipogenesis and restricting dietary fats, such as caprylic acid, may help overcome treatment resistance in patients with T-ALL exhibiting low mitochondrial activity. TRIAL REGISTRATION: The clinical trial was registered under the identifiers ChiCTR-ONRC-14004968 and ChiCTR2000031553 at ClinicalTrials.gov.
Adult↗
Machine learning algorithm-based biomarker exploration and validation of mitochondria-related diagnostic genes in osteoarthritis.
The role of mitochondria in the pathogenesis of osteoarthritis (OA) is significant. In this study, we aimed to identify diagnostic signature genes associated with OA from a set of mitochondria-related genes (MRGs). First, the gene expression profiles of OA cartilage GSE114007 and GSE57218 were obtained from the Gene Expression Omnibus. And the limma method was used to detect differentially expressed genes (DEGs). Second, the biological functions of the DEGs in OA were investigated using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Wayne plots were employed to visualize the differentially expressed mitochondrial genes (MDEGs) in OA. Subsequently, the LASSO and SVM-RFE algorithms were employed to elucidate potential OA signature genes within the set of MDEGs. As a result, GRPEL and MTFP1 were identified as signature genes. Notably, GRPEL1 exhibited low expression levels in OA samples from both experimental and test group datasets, demonstrating high diagnostic efficacy. Furthermore, RT-qPCR analysis confirmed the reduced expression of Grpel1 in an in vitro OA model. Lastly, ssGSEA analysis revealed alterations in the infiltration abundance of several immune cells in OA cartilage tissue, which exhibited correlation with GRPEL1 expression. Altogether, this study has revealed that GRPEL1 functions as a novel and significant diagnostic indicator for OA by employing two machine learning methodologies. Furthermore, these findings provide fresh perspectives on potential targeted therapeutic interventions in the future.
Humans↗
The role of mitochondria in sex- and age-specific gene expression in a species without sex chromosomes.
Mitochondria perform an array of functions, many of which involve interactions with gene products encoded by the nucleus. These mitochondrial functions, particularly those involving energy production, can be expected to differ between sexes and across ages. Here, we measured mitochondrial effects on sex- and age-specific gene expression in parental and reciprocal F1 hybrids between allopatric populations of Tigriopus californicus with over 20% mitochondrial DNA divergence. Because the species lacks sex chromosomes, sex-biased mitochondrial effects are not confounded by the effects of sex chromosomes. Results revealed pervasive sex differences in mitochondrial effects, including effects on energetics and aging involving nuclear interactions throughout the genome. Using single-individual RNA sequencing, sex differences were found to explain more than 80% of the variance in gene expression. Males had higher expression of mitochondrial genes and mitochondrially targeted proteins (MTPs) involved in oxidative phosphorylation (OXPHOS), while females had elevated expression of non-OXPHOS MTPs, indicating strongly sex-dimorphic energy metabolism at the whole organism level. Comparison of reciprocal F1 hybrids allowed insights into the nature of mito-nuclear interactions, showing both mitochondrial effects on nuclear expression, and nuclear effects on mitochondrial expression. While based on a small set of crosses, sex-specific increases in mitochondrial expression with age were associated with longer life. Network analyses identified nuclear components of strong mito-nuclear interactions and found them to be sexually dimorphic. These results highlight the profound impact of mitochondria and mito-nuclear interactions on sex- and age-specific gene expression.
Animals↗
Pathogenic POLRMT variants in mice impair mtDNA transcription and affect perinatal survival.
Mitochondrial gene expression is essential for oxidative phosphorylation that generates the bulk of the cellular ATP, and mitochondrial dysfunction is a common cause of human metabolic diseases. Recently, the first pathogenic variants in the only known mitochondrial RNA polymerase (POLRMT) were described in patients presenting with a wide variety of clinical manifestations, including hypotonia, short stature, and developmental delay. Here, we modeled two human pathogenic POLRMT variants by creating the corresponding substitutions in mice: the dominant S582F and the recessive R984C variant. Mice homozygous for the R984C variant showed perinatal lethality without apparent embryonic developmental defects, a finding consistent with a failure to adapt to the metabolic transition to oxidative metabolism at birth. Mice carrying the S582F variant were viable and exhibited decreased mitochondrial transcript levels due to impaired de novo transcription. However, mtDNA levels and in organello mtDNA replication remained normal, which recapitulates the molecular phenotypes observed in patients. Altogether, our findings indicate that the conserved arginine near the active site is essential for POLRMT function, while the serine in the intercalating hairpin of the N-terminal domain is required for near-genome length transcription but not primase activity. This study highlights genotype-phenotype differences and provides new insights into POLRMT function.
Animals↗
m6A-Mediated epitranscriptomic control of mitochondrial dysfunction in neurodegeneration.
Mitochondrial dysfunction is a common pathology of neurodegenerative diseases, which contributes to neuronal vulnerability via excessive oxidative stress, impaired bioenergetics, and dysregulated apoptosis. Emerging studies highlighted the critical role of epitranscriptomic RNA modifications, particularly N6-methyladenosine (m6A), in mitochondrial gene expression regulation and cellular stress responses. m6A modifications are installed by methyltransferases ("writers," METTL3/METTL14), recognized by reader proteins (YTH domain family proteins, IGF2BPs), and removed by demethylases ("erasers," FTO, ALKBH5), collectively orchestrating mRNA splicing, localization, stability, and translation. Recent evidence demonstrates that m6A modifications modulate both nuclear-encoded and mitochondrially encoded transcripts and regulate key mitochondrial processes, including fission/fusion dynamics, oxidative phosphorylation, mitophagy, and apoptosis. Dysregulation of m6A machinery disrupts mitochondrial homeostasis, exacerbates oxidative stress and neuroinflammation, and promotes neuronal loss. Importantly, pharmacological or genetic modulation of m6A regulators can restore mitochondrial function, inhibit caspase activation, and dampen pro-inflammatory signaling, underscoring their therapeutic potential. This review consolidates current insights into mitochondrial epitranscriptomics, emphasizing how m6A modifications act as central regulators of mitochondrial stress responses and neurodegeneration.
Humans↗
Transcription maps of mtDNAs of two strains of saccharomyces: transcription of strain-specific insertions; Complex RNA maturation and splicing.
We have developed a two-dimensional method for simultaneously mapping on the yeast mtDNA genome all the transcripts representing more than 0.01% of mtRNA. In two yeast strains, Saccharomyces carlsbergensis NCYC-74 and Saccharomyces cerevisiae KL14-4A, about 25 discrete transcripts were found apart from tRNAs. The mtDNAs of these strains differ by the absence (NCYC-74) or presence (KL 14-4A) of various large insertions located within genetically active regions. The transcripts can all be related to known loci on the genetic map. In nearly all cases the RNAs are much longer than required to specify the known protein product of the locus concerned. The organization of the transcripts is similar in the two strains except at the positions of the large insertions (500-3300 bp) in the oxi-3 and cob loci. The sequences of these insertions are present in RNA species larger than 25S, but are absent from smaller transcripts of the same regions. This is probably due to splicing, since the coding sequences for most of these smaller transcripts are noncontiguous. The smaller transcripts of other loci also seem to arise from processing of larger RNA species. The oxi-3 locus, containing the structural gene for cytochrome c oxidase subunit l, is transcribed in a very complex fashion that suggests differential splicing into partially overlapping transcripts. This may indicate that oxi-3 has additional genetic functions, including possible control of the biosynthesis of cytochrome c oxidase holoenzyme or its assembly into the mitochondrial inner membrane. As in the case of the eucaryote nucleus, the regulation of mitochondrial gene expression seems to occur more at the level of RNA processing than has been recognized thus far.
Chromosome Mapping↗
Metabolites with a message: impacts on epigenetics and implications for epimetabopathies.
Once identified primarily as a bioenergetic organelle, the mitochondrion has now emerged as a pivotal signalling hub that communicates with the nucleus to shape cellular fate. It integrates the cell's metabolic state with transcriptional and epigenetic programs, tweaking gene expression. Mitochondrial metabolites serve as regulators of cellular physiology, functioning as important signalling intermediates and modulating enzymes involved in epigenetic modifications. In parallel, nuclear transcriptional programs govern mitochondrial biogenesis, dynamics and quality control to preserve metabolic homeostasis under stress. Moreover, circulating metabolites can function as systemic messengers coordinating interorgan crosstalk and immune responses. Perturbations in this dynamic reciprocity can rewire the cellular script and spiral into "epimetabopathies", where metabolic-epigenetic conflicts ignite pathological conditions. This review discusses how mitochondria-nucleus crosstalk coordinates genome surveillance, metabolite-driven epigenetic regulation and systemic metabolic signalling. It further offers an overview of epimetabopathies with potential implications for future diagnostics and therapeutics.
Humans↗
Expression and mutation characteristics of mitochondrial genes in PBMCs of SLE patients: Implications for SLE pathogenesis.
This study aimed to investigate mitochondrial gene mutations and expression in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) patients, focusing on MT-ND5, and assess expression changes under lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α), and dexamethasone stimulation. Peripheral blood was collected from female SLE patients. Mitochondrial DNA (mtDNA) from PBMCs was sequenced using the HiSeq PE150 platform. Quantitative reverse transcription PCR and western blotting were used to evaluate mRNA and protein expression of the most frequently mutated mitochondrial genes. Cultured PBMCs were treated with LPS, TNF-α, or dexamethasone to examine regulatory effects. A total of 589 mtDNA mutation sites were detected in SLE patients. Among 13 protein-coding genes, MT-ND5, MT-CYB, MT-CO1, MT-ND4, and MT-CO3 exhibited the highest mutation frequencies. Expression analysis revealed significantly reduced mRNA and protein levels of these genes in SLE PBMCs compared with controls, with further decreases after stimulation with LPS, TNF-α, or dexamethasone. SLE PBMCs display extensive mitochondrial mutations and downregulation of key genes, particularly MT-ND5. Inflammatory and therapeutic stimuli exacerbate this suppression, suggesting mitochondrial dysfunction contributes to SLE susceptibility and progression.
Humans↗
Expression of petite mitochondrial DNA in vivo: zygotic gene rescue.
A protocol is introduced for probing the organization and regulation of expression of the yeast mitochondrial genome, termed "zygotic gene rescue." The procedure is based on the notion that genes retained on mitochondrial DNA of on the notion that genes retained on mitochondrial DNA of petites can be expressed in zygotes of a cross between petite and wild type. To test the validity of this notion, we have taken advantage of our ability to discriminate, by mobility differences on sodium dodecyl sulfate/polyacrylamide gels, different forms of the product of alleles of the mitochondrial gene, varI. In petite strains that have retained the varI gene, its characteristic product appears in zygotes 4-5 hr after mating; no product is observed in petite strains deleted in the varI locus. Our studies indicate that (i) expression in the zygote of the varI gene in the petite genome is not exclusively the result of recombination with mitochondrial DNA of the wild-type tester, and (ii) the varI gene is probably reiterated in the petite mitochondrial genome. The strength of the technique of zygotic gene rescue in the analysis of the mitochondrial genome is discussed.
Alleles↗
"Tissue-specific mitochondrial dysfunction in keratoconus: An integrated structural, genomic, and functional analysis".
PURPOSE: Keratoconus (KC) is a progressive corneal ectasia characterized by stromal thinning, conical protrusion, and irregular astigmatism, leading to visual impairment. Although oxidative stress is implicated in KC, the role of mitochondrial dysfunction remains unclear. We evaluated mitochondrial structural, genomic, and functional abnormalities in corneal tissues and blood from KC patients. METHODS: This prospective study enrolled 110 KC patients and 55 controls. Transmission electron microscopy (TEM) and immunohistochemistry (IHC) were performed on epithelial and stromal tissues from 10 KC to 5 control corneas assessing mitochondrial morphology, oxidative phosphorylation (OXPHOS) complexes and pro-apoptotic protein NOXA. Whole mitochondrial DNA (mtDNA) sequencing and relative mtDNA copy number analysis were performed on paired blood and corneal tissues from 50 KC patients and 35 controls including both epithelial and stromal samples. Gene expression of mitochondrial biogenesis and oxidative stress-related genes was analysed by qRT-PCR in corneal epithelium from independent 50 KC patients and 15 controls. RESULTS: TEM revealed cristolysis, membrane disruption, and reduced mitochondrial density in KC corneas. IHC showed reduced expression of OXPHOS complexes and increased NOXA expression (p < 0.05). Sequencing identified 1107 mtDNA variants, with more variants in corneal tissues than matched blood (929 vs. 576; p = 0.0002). Recurrent likely pathogenic variants were enriched in complex I-encoding genes (ND4, ND5). KC corneas showed reduced mtDNA copy number, downregulated POLRMT, upregulated NOX4, and significant downregulation of multiple antioxidant genes (p < 0.0001). CONCLUSION: KC patients exhibit tissue-specific mitochondrial abnormalities and impaired oxidative stress regulation, supporting a role for mitochondrial dysfunction in disease pathogenesis and highlighting potential therapeutic targets.
Corneal pathology↗
The human mitochondrial genome contains a second light strand promoter.
The human mitochondrial genome must be replicated and expressed in a timely manner to maintain energy metabolism and supply cells with adequate levels of adenosine triphosphate. Central to this process is the idea that replication primers and gene products both arise via transcription from a single light strand promoter (LSP) such that primer formation can influence gene expression, with no consensus as to how this is regulated. Here, we report the discovery of a second light strand promoter (LSP2) in humans, with features characteristic of a bona fide mitochondrial promoter. We propose that the position of LSP2 on the mitochondrial genome allows replication and gene expression to be orchestrated from two distinct sites, which expands our long-held understanding of mitochondrial gene expression in humans.
Adenosine Triphosphate↗
Effect of gene dosage on expression of mitochondrial malic enzyme activity in the mouse.
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Albinism↗
Identification and validation of prognostic genes associated with mitochondrial nuclear genes in gastric cancer.
Mitochondrial-related nuclear genes (MNGs) have shown great importance in cancer diagnosis and prognosis, but their role in gastric cancer (GC) remains unclear. GC-related transcriptome data from the gene expression omnibus and cancer genome atlas databases were analyzed to identify differentially expressed MNGs. A prognostic risk model was constructed through univariate Cox and least absolute shrinkage and selection operator regression, validated by Kaplan-Meier (K-M) survival curve and receiver operating characteristic curve. This was followed by immune infiltration analysis, independent prognostic analysis, functional enrichment analysis, drug sensitivity analysis, drug prediction, molecular docking and construction of regulatory networks. Three prognostic genes (ATP8A2, COX15 and TARS2) were identified. The expression of TARS2 and COX15 was positively correlated with CNV, while ATP8A2 was unaffected. The risk model and nomogram, integrating risk score and clinicopathological factors, exhibited excellent predictive performance. A significant correlation was observed between prognostic genes and differential immune cells, such as T cells, B cells, and NK cells. BMS-754807, Gefitinib, JQ1, Lapatinib, and Sapitinib exhibited significant differences in sensitivity between the high-risk group and the low-risk group. The results of molecular docking showed TP8A2 has stable binding ability with cytosine, COX15 with indomethacin, and TARS2 with bisacodyl. RT-qPCR revealed downregulation of ATP8A2 and upregulation of COX15 and TARS2 in GC samples. MNGs, including ATP8A2, COX15, and TARS2, demonstrated significant associations with immune infiltration, CNV, and prognostic outcomes of GC.
Humans↗
Stress-induced altered expression of hippocampal nuclear and mitochondrial encoded genes in rats and cross-species genetic associations reveal molecular links to depression.
BACKGROUND: Mitochondria play a pivotal role in energy production, and their dysfunction not only hampers cells' ability to meet energy requirements but also contributes to the impairment of neural plasticity, a critical feature of depressive disorders. In this study, mitochondrial cross-omics analysis was carried out in the hippocampus of restraint rats to understand the role of mitochondria in depression pathophysiology. METHODS: The expression profiles of hippocampal mitochondrial and nuclear-encoded genes in mitochondrial fractions from restraint and handled control rats were obtained using high-throughput RNA sequencing. Weighted gene co-expression network analysis (WGCNA) was used to identify the gene co-expression and pathways associated with the restraint phenotype. Mutual Information Network algorithm tools Arance, CLR, and MRNET were additionally used to screen the functional modules and hub genes and their similarity with the WGCNA-based network analysis. Finally, cross-species homology followed by gene association analysis was conducted to obtain SNPs and haplotypes related to depression phenotype. RESULTS: A significant proportion of mitochondrial and nuclear-encoded genes showed differential regulation in the hippocampus of restraint rats. WGCNA and Mutual Information Network analysis yielded distinct functional modules significantly related to restraint phenotype. Further network analysis revealed distinct co-expression patterns associated with differentially expressed genes associated with these modules. Cross-species analysis showed 39 significantly associated SNPs with the depression phenotype, where the most significant SNP, rs10899570, was located within the TENM4 gene. Further, rs1573529 and rs10899570 were distributed into the linkage disequilibrium block where SNPs were highly correlated. Subsequent haplotype analysis showed that rs1573529 and rs10899570 were significantly associated with depressive behavior. CONCLUSIONS: The study demonstrates a significant impact of restraint stress on mitochondrial functions and genetic association, suggesting their critical role in depression pathophysiology.
Animals↗
TTC19 and FMNL2 gene variants in a pediatric case of mitochondrial disorder with renal tubular acidosis.
Mitochondrial complex III deficiency caused by pathogenic variants in TTC19 is a heterogeneous disorder typically presenting with progressive neurological involvement in late childhood. Early-onset of disease with predominant renal manifestations are uncommon and may complicate diagnosis. We report a child presenting with developmental delay, failure to thrive, lactic acidosis, and distal renal tubular acidosis (dRTA), raising suspicion of an underlying mitochondrial disorder. Whole exome sequencing (WES) analysis identified a homozygous intron-exon boundary deletion of 31 bp (c.463-19_474del) in TTC19 predicted to disrupt splicing, with functional evidence demonstrating aberrant transcript formation, reduced gene expression, and mitochondrial dysfunction in patient-derived fibroblasts. Based on the biochemical findings, re-analysis of exome data revealed a novel homozygous canonical splice-site variant (c.783-1G>A) in FMNL2. The splicing assay showed the skipping of exon 9, and reduced expression in the fibroblasts. This case expands the clinical spectrum of TTC19-related mitochondrial complex III deficiency with early-onset renal tubular acidosis. While TTC19 is the most plausible primary disease-causing gene, the functional disruption of FMNL2 suggests a potential contributory role or association with the renal phenotype. Hence, these findings highlight the importance of genomic re-analysis along with functional studies in resolving complex multisystem disorders.
Female↗
Assignment of a gene necessary for the expression of mitochondrial glutamic-oxaloacetic transaminase in human-mouse hybrid cells.
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Animals↗
[Cis expression, at complementation, of mitochondrial mosaic gene exons regulating cytochrome b in Saccharomyces cerevisiae (proceedings)].
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Cytochromes↗