Why All the Fuss about Oxidative Phosphorylation (OXPHOS)?
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ABSTRACT:
SUBMITTER: Xu Y
PROVIDER: S-EPMC9298160 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe primary energy-producing pathway in eukaryotic cells, the oxidative phosphorylation (OXPHOS) system, comprises proteins encoded by both mitochondrial and nuclear genes. To maintain the function of the OXPHOS system, the pattern of substitutions in mitochondrial and nuclear genes may not be completely independent. It has been suggested that slightly deleterious substitutions in mitochondrial genes are compensated by substitutions in the interacting nuclear genes due to positive selection. Among the four largest insect orders, Coleoptera (beetles), Hymenoptera (sawflies, wasps, ants, and bees), Diptera (midges, mosquitoes, and flies) and Lepidoptera (moths and butterflies), the mitochondrial genes of Hymenoptera exhibit an exceptionally high amino acid substitution rate while the evolution of nuclear OXPHOS genes is largely unknown. Therefore, Hymenoptera is an excellent model group for testing the hypothesis of positive selection driving the substitution rate of nuclear OXPHOS genes. In this study, we report the evolutionary rate of OXPHOS genes in Hymenoptera and test for evidence of positive selection in nuclear OXPHOS genes of Hymenoptera.ResultsOur analyses revealed that the amino acid substitution rate of mitochondrial and nuclear OXPHOS genes in Hymenoptera is higher than that in other studied insect orders. In contrast, the amino acid substitution rate of non-OXPHOS genes in Hymenoptera is lower than the rate in other insect orders. Overall, we found the dN/dS ratio of the nuclear OXPHOS genes to be higher in Hymenoptera than in other insect orders. However, nuclear OXPHOS genes with high dN/dS ratio did not always exhibit a high amino acid substitution rate. Using branch-site and site model tests, we identified various codon sites that evolved under positive selection in nuclear OXPHOS genes.ConclusionsOur results showed that nuclear OXPHOS genes in Hymenoptera are evolving faster than the genes in other three insect orders. The branch test suggested that while some nuclear OXPHOS genes in Hymenoptera show a signature of positive selection, the pattern is not consistent across all nuclear OXPHOS genes. As only few codon sites were under positive selection, we suggested that positive selection might not be the only factor contributing to the rapid evolution of nuclear OXPHOS genes in Hymenoptera.
| S-EPMC5745899 | biostudies-literature
Project description:The ability to generate and detect electric fields has evolved in several groups of fishes as a means of communication, navigation and, occasionally, predation. The energetic burden required can account for up to 20% of electric fishes' daily energy expenditure. Despite this, molecular adaptations that enable electric fishes to meet the metabolic demands of bioelectrogenesis remain unknown. Here, we investigate the molecular evolution of the mitochondrial oxidative phosphorylation (OXPHOS) complexes in the two most diverse clades of weakly electric fishes-South American Gymnotiformes and African Mormyroidea, using codon-based likelihood approaches. Our analyses reveal that although mitochondrial OXPHOS genes are generally subject to strong purifying selection, this constraint is significantly reduced in electric compared to non-electric fishes, particularly for complexes IV and V. Moreover, analyses of concatenated mitochondrial genes show strong evidence for positive selection in complex I genes on the two branches associated with the independent evolutionary origins of electrogenesis. These results suggest that adaptive evolution of proton translocation in the OXPHOS cellular machinery may be associated with the evolution of bioelectrogenesis. Overall, we find striking evidence for remarkably similar effects of electrogenesis on the molecular evolution of mitochondrial OXPHOS genes in two independently derived clades of electrogenic fishes. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.
| S-EPMC6939368 | biostudies-literature
Project description:Friedreich ataxia (FRDA) is the most frequent progressive autosomal recessive disorder associated with unstable expansion of GAA trinucleotide repeats in the first intron of the FXN gene, which encodes for the mitochondrial frataxin protein. The number of repeats correlates with disease severity, where impaired transcription of the FXN gene results in reduced expression of the frataxin protein. Gene expression studies provide insights into disease pathogenicity and identify potential biomarkers, an important goal of translational research in neurodegenerative diseases. Here, using real-time PCR (RT-PCR), the expression profiles of mitochondrial (mtDNA) and nuclear DNA (nDNA) genes that encode for the mitochondrial subunits of respiratory oxidative phosphorylation (OXPHOS) complex I in the blood panels of 21 FRDA patients and 24 healthy controls were investigated. Here, the expression pattern of mtDNA-encoded complex I subunits was distinctly different from the expression pattern of nDNA-encoded complex I subunits, where significant (p<0.05) down-regulation of the mitochondrial ND2, ND4L, and ND6 complex I genes, compared to controls, were observed. In addition, the expression pattern of one nDNA-encoded gene, NDUFA1, was significantly (p<0.05) down-regulated compared to control. These findings suggest, for the first time, that the regulation of complex I subunit expression in FRDA is complex, rather than merely being a reflection of global co-regulation, and may provide important clues toward novel therapeutic strategies for FRDA and mitochondrial complex I deficiency.
| S-EPMC3976380 | biostudies-literature
Project description:Fig wasps are a peculiar group of insects which, for millions of years, have inhabited the enclosed syconia of fig trees. Considering the relatively closed and dark environment of fig syconia, we hypothesize that the fig wasps' oxidative phosphorylation (OXPHOS) pathway, which is the main oxygen consumption and adenosine triphosphate (ATP) production system, may have adaptively evolved. In this study, we manually annotated the OXPHOS genes of 11 species of fig wasps, and compared the evolutionary patterns of OXPHOS genes for six pollinators and five non-pollinators. Thirteen mitochondrial protein-coding genes and 30 nuclear-coding single-copy orthologous genes were used to analyze the amino acid substitution rate and natural selection. The results showed high amino acid substitution rates of both mitochondrial and nuclear OXPHOS genes in fig wasps, implying the co-evolution of mitochondrial and nuclear genes. Our results further revealed that the OXPHOS-related genes evolved significantly faster in pollinators than in non-pollinators, and five genes had significant positive selection signals in the pollinator lineage, indicating that OXPHOS genes play an important role in the adaptation of pollinators. This study can help us understand the relationship between gene evolution and environmental adaptation.
| S-EPMC7697784 | biostudies-literature
Project description:Tumor cell metabolism is altered during leukemogenesis. Cells performing oxidative phosphorylation (OXPHOS) generate reactive oxygen species (ROS) through mitochondrial activity. To limit the deleterious effects of excess ROS, certain gene promoters contain antioxidant response elements (ARE), e.g. the genes NQO-1 and HO-1. ROS induces conformational changes in KEAP1 and releases NRF2, which activates AREs. We show in vitro and in vivo that OXPHOS induces, both in primary leukemic cells and cell lines, de novo expression of NQO-1 and HO-1 and also the MAPK ERK5 and decreases KEAP1 mRNA. ERK5 activates the transcription factor MEF2, which binds to the promoter of the miR-23a-27a-24-2 cluster. Newly generated miR-23a destabilizes KEAP1 mRNA by binding to its 3'UTR. Lower KEAP1 levels increase the basal expression of the NRF2-dependent genes NQO-1 and HO-1. Hence, leukemic cells performing OXPHOS, independently of de novo ROS production, generate an antioxidant response to protect themselves from ROS.
| S-EPMC4739420 | biostudies-literature
Project description:BackgroundIn eukaryotic cells, oxidative phosphorylation (OXPHOS) uses the products of both nuclear and mitochondrial genes to generate cellular ATP. Interspecies comparative analysis of these genes, which appear to be under strong functional constraints, may shed light on the evolutionary mechanisms that act on a set of genes correlated by function and subcellular localization of their products.ResultsWe have identified and annotated the Drosophila melanogaster, D. pseudoobscura and Anopheles gambiae orthologs of 78 nuclear genes encoding mitochondrial proteins involved in oxidative phosphorylation by a comparative analysis of their genomic sequences and organization. We have also identified 47 genes in these three dipteran species each of which shares significant sequence homology with one of the above-mentioned OXPHOS orthologs, and which are likely to have originated by duplication during evolution. Gene structure and intron length are essentially conserved in the three species, although gain or loss of introns is common in A. gambiae. In most tissues of D. melanogaster and A. gambiae the expression level of the duplicate gene is much lower than that of the original gene, and in D. melanogaster at least, its expression is almost always strongly testis-biased, in contrast to the soma-biased expression of the parent gene.ConclusionsQuickly achieving an expression pattern different from the parent genes may be required for new OXPHOS gene duplicates to be maintained in the genome. This may be a general evolutionary mechanism for originating phenotypic changes that could lead to species differentiation.
| S-EPMC551531 | biostudies-literature
Project description:The helicase-like transcription factor (HLTF) gene-a tumor suppressor in human colorectal cancer (CRC)-is regulated by alternative splicing and promoter hypermethylation. In this study, we used the AOM/DSS-induced mouse model to show Hltf-deletion caused poor survival concomitant with increased tumor multiplicity, and dramatically shifted the topographic distribution of lesions into the rectum. Differential isoform expression analysis revealed both the truncated isoform that lacks a DNA-repair domain and the full length isoform capable of DNA damage repair are present during adenocarcinoma formation in controls. iPathwayGuide identified 51 dynamically regulated genes of 10,967 total genes with measured expression. Oxidative Phosphorylation (Kegg: 00190), the top biological pathway perturbed by Hltf-deletion, resulted from increased transcription of Atp5e, Cox7c, Uqcr11, Ndufa4 and Ndufb6 genes, concomitant with increased endogenous levels of ATP (p = 0.0062). Upregulation of gene expression, as validated with qRT-PCR, accompanied a stable mtDNA/nDNA ratio. This is the first study to show Hltf-deletion in an inflammation-associated CRC model elevates mitochondrial bioenergetics.
| S-EPMC6713344 | biostudies-literature
Project description:Preclinical models suggest anticancer activity of IM156, a novel biguanide mitochondrial protein complex 1 inhibitor of oxidative phosphorylation (OXPHOS). This first-in-human dose-escalation study enrolled patients with refractory advanced solid tumors to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Eligible patients received oral IM156 every other day (QOD) or daily (QD) and were assessed for safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary signals of efficacy. 22 patients with advanced cancers (gastric, n = 8; colorectal, n = 3; ovarian, n = 3; other, n = 8) received IM156 100 to 1,200 mg either QOD or QD. There were no DLTs. However, 1,200 mg QD was not well tolerated due to nausea; 800 mg QD was determined as the RP2D. The most frequent treatment-related AEs (TRAEs) were nausea (n = 15; 68%), diarrhea (n = 10; 46%), emesis (n = 9; 41%), fatigue (n = 4; 18%) and abdominal pain, constipation, and blood lactate increased (n = 2 each; 9%). Grade 3 nausea (n = 3; 14%) was the only grade ≥ 3 TRAE. Plasma exposures increased dose proportionally; mean Day 27 area under the curve (AUC0-24) values were higher following QD administration compared to the respective QOD regimen. Stable disease (SD), observed in 7 (32%) patients (confirmed in 2 [9%]), was the best response. To our knowledge, this is the first phase 1 study of an OXPHOS inhibitor that established a RP2D for further clinical development in cancer. Observed AEs of IM156 were manageable and SD was the best response.
| S-EPMC9395488 | biostudies-literature
Project description:The helicase-like transcription factor (HLTF) gene – a tumor suppressor in human colorectal cancer (CRC) - is regulated by alternative splicing and promoter hypermethylation. The detection of hypermethylated HLTF DNA in fecal occult blood tests is an indicator of disease recurrence and poor survival. Hltf-deficiency in the ApcMin/+ mouse strain increased the formation of intestinal adenocarcinoma with a high incidence of gross chromosomal instabilities. To investigate Hltf-deletion effects in CRC without cross-breeding into a tumorigenic strain, Hltf-deletion was studied in mice treated with the carcinogen azoxymethane (AOM) and the proinflammatory agent dextran sulfate (DSS). Hltf-deletion resulted in weight loss beginning at treatment week 6, and poor survival (Kaplan-Meier survival plot). Hltf-deletion increased tumor multiplicity compared to controls, and dramatically shifted the topographic distribution of lesions into the rectum. Differential isoform expression analysis of lesions from control mice revealed both the truncated isoform that lacks a DNA-repair domain and the full length isoform capable of DNA damage repair are present (3:1.8 ratio) during adenocarcinoma formation. iPathwayGuide identified 51 dynamically regulated genes of 10,967 total genes with measured expression. Oxidative Phosphorylation (Kegg: 00190), the top biological pathway (p=0.006; p value correction: Bonferroni) perturbed by Hltf-deletion, resulted from increased transcription of Atp5e, Cox7c, Uqcr11, Ndufa4 and Ndufb6 genes, concomitant with increased endogenous levels of ATP (p=0.0176). Upregulation of gene expression, as validated with qRT-PCR, was accompanied by a stable mtDNA/nDNA ratio. This is the first study to show Hltf-deletion in an inflammation-associated CRC model elevates mitochondrial bioenergetics. The distal shift in tumorigenesis indicates the detection of hypermethylated HLTF DNA in human stool samples might be a prognostic biomarker for distal (left-sided) colorectal cancer rather than proximal (right-sided) colon cancer.
2019-06-18 | GSE132814 | GEO
Project description:Dermal invasion is a hallmark of malignant melanoma. The molecular alterations driving the progression of primary melanoma to metastatic disease have been studied extensively, whereas the early progression of non-invasive primary melanoma to an invasive state is not well understood. To elucidate the mechanisms underlying the transition from radial to vertical growth, the first step in melanoma invasion, we developed a zebrafish melanoma model in which constitutive activation of ribosomal protein S6 kinase 1 (RSK1) drives tumor invasion. Transcriptomic analysis of RSK1-activated tumors identified metabolic changes, including upregulation of genes associated with oxidative phosphorylation. Vertical growth phase human melanoma cells show higher oxygen consumption and preferential utilization of glutamine compared to radial growth phase melanoma cells. Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1a has been proposed as a master regulator of tumor oxidative phosphorylation. In human primary melanoma specimens we show that PGC1a protein expression is positively associated with increased tumor thickness and expression of the proliferative marker Ki-67 and the reactive oxygen species (ROS) scavenger SCARA3. PGC1a depletion modulates cellular processes associated with primary melanoma growth and invasion, including oxidative stress. Our results support a role for PGC1a in mediating glutamine-driven OXPHOS to facilitate the invasive growth of primary melanoma.
2020-01-24 | GSE144117 | GEO