Role of mitochondrial genetic interactions in determining adaptation to high altitude human population.

Physiological and haplogroup studies performed to understand high-altitude adaptation in humans are limited to individual genes and polymorphic sites. Due to stochastic evolutionary forces, the frequency of a polymorphism is affected by changes in the frequency of a near-by polymorphism on the same DNA sample making them connected in terms of evolution. Here, first, we provide a method to model these mitochondrial polymorphisms as "co-mutation networks" for three high-altitude populations, Tibetan, Ethiopian and Andean. Then, by transforming these co-mutation networks into weighted and undirected gene-gene interaction (GGI) networks, we were able to identify functionally enriched genetic interactions of CYB and CO3 genes in Tibetan and Andean populations, while NADH dehydrogenase genes in the Ethiopian population playing a significant role in high altitude adaptation. These co-mutation based genetic networks provide insights into the role of different set of genes in high-altitude adaptation in human sub-populations.

New Insights Into Mitochondrial Dysfunction at Disease Susceptibility Loci in the Development of Type 2 Diabetes.

This study investigated the potential genetic mechanisms which underlie adipose tissue mitochondrial dysfunction in Type 2 diabetes (T2D), by systematically identifying nuclear-encoded mitochondrial genes (NEMGs) among the genes regulated by T2D-associated genetic loci. The target genes of these 'disease loci' were identified by mapping genetic loci associated with both disease and gene expression levels (expression quantitative trait loci, eQTL) using high resolution genetic maps, with independent estimates co-locating to within a small genetic distance. These co-locating signals were defined as T2D-eQTL and the target genes as T2D cis-genes. In total, 763 cis-genes were associated with T2D-eQTL, of which 50 were NEMGs. Independent gene expression datasets for T2D and insulin resistant cases and controls confirmed that the cis-genes and cis-NEMGs were enriched for differential expression in cases, providing independent validation that genetic maps can identify informative functional genes. Two additional results were consistent with a potential role of T2D-eQTL in regulating the 50 identified cis-NEMGs in the context of T2D risk: (1) the 50 cis-NEMGs showed greater differential expression compared to other NEMGs and (2) other NEMGs showed a trend towards significantly decreased expression if their expression levels correlated more highly with the subset of 50 cis-NEMGs. These 50 cis-NEMGs, which are differentially expressed and associated with mapped T2D disease loci, encode proteins acting within key mitochondrial pathways, including some of current therapeutic interest such as the metabolism of branched-chain amino acids, GABA and biotin.

An evolutionarily diverged mitochondrial protein controls biofilm growth and virulence in Candida albicans.

A forward genetic screening approach identified orf19.2500 as a gene controlling Candida albicans biofilm dispersal and biofilm detachment. Three-dimensional (3D) protein modeling and bioinformatics revealed that orf19.2500 is a conserved mitochondrial protein, structurally similar to, but functionally diverged from, the squalene/phytoene synthases family. The C. albicans orf19.2500 is distinguished by 3 evolutionarily acquired stretches of amino acid inserts, absent from all other eukaryotes except a small number of ascomycete fungi. Biochemical assays showed that orf19.2500 is required for the assembly and activity of the NADH ubiquinone oxidoreductase Complex I (CI) of the respiratory electron transport chain (ETC) and was thereby named NDU1. NDU1 is essential for respiration and growth on alternative carbon sources, important for immune evasion, required for virulence in a mouse model of hematogenously disseminated candidiasis, and for potentiating resistance to antifungal drugs. Our study is the first report on a protein that sets the Candida-like fungi phylogenetically apart from all other eukaryotes, based solely on evolutionary "gain" of new amino acid inserts that are also the functional hub of the protein.

Alterations in Mitochondrial Dynamic-related Genes in the Peripheral Blood of Alzheimer's Disease Patients.

BACKGROUND: Mitochondrial dysfunction is a pathological feature that manifests early in the brains of patients with Alzheimer's Disease (AD). The disruption of mitochondrial dynamics contributes to mitochondrial morphological and functional impairments. Our previous study demonstrated that the expression of genes involved in amyloid beta generation was altered in the peripheral blood of AD patients. OBJECTIVE: The aim of this study was to further investigate the relative levels of mitochondrial genes involved in mitochondrial dynamics, including mitochondrial fission and fusion, and mitophagy in peripheral blood samples from patients with AD compared to healthy controls. METHODS: The mRNA levels were analyzed by real-time polymerase chain reaction. Gene expression profiles were assessed in relation to cognitive performance. RESULTS: Significant changes were observed in the mRNA expression levels of fission-related genes; Fission1 (FIS1) levels in AD subjects were significantly higher than those in healthy controls, whereas Dynamin- related protein 1 (DRP1) expression was significantly lower in AD subjects. The levels of the mitophagy-related genes, PTEN-induced kinase 1 (PINK1) and microtubule-associated protein 1 light chain 3 (LC3), were significantly increased in AD subjects and elderly controls compared to healthy young controls. The mRNA levels of Parkin (PARK2) were significantly decreased in AD. Correlations were found between the expression levels of FIS1, DRP1 and PARK2 and cognitive performance scores. CONCLUSION: Alterations in mitochondrial dynamics in the blood may reflect impairments in mitochondrial functions in the central and peripheral tissues of AD patients. Mitochondrial fission, together with mitophagy gene profiles, might be potential considerations for the future development of blood-based biomarkers for AD.

Hidden cases of tRNA gene duplication and remolding in mitochondrial genomes of amphipods.

The evolution of tRNA genes in mitochondrial (mt) genomes is a complex process that includes duplications, degenerations, and transpositions, as well as a specific process of identity change through mutations in the anticodon (tRNA gene remolding or tRNA gene recruitment). Using amphipod-specific tRNA models for annotation, we show that tRNA duplications are more common in the mt genomes of amphipods than what was revealed by previous annotations. Seventeen cases of tRNA gene duplications were detected in the mt genomes of amphipods, and ten of them were tRNA genes that underwent remolding. The additional tRNA gene findings were verified using phylogenetic analysis and genetic distance analysis. The majority of remolded tRNA genes (seven out of ten cases) were found in the mt genomes of endemic amphipod species from Lake Baikal. All additional mt tRNA genes arose independently in the Baikalian amphipods, indicating the unusual plasticity of tRNA gene evolution in these species assemblages. The possible reasons for the unusual abundance of additional tRNA genes in the mt genomes of Baikalian amphipods are discussed. The amphipod-specific tRNA models developed for MiTFi refine existing predictions of tRNA genes in amphipods and reveal additional cases of duplicated tRNA genes overlooked by using less specific Metazoa-wide models. The application of these models for mt tRNA gene prediction will be useful for the correct annotation of mt genomes of amphipods and probably other crustaceans.

Evolutionary genomics analysis of human nucleus-encoded mitochondrial genes: implications for the roles of energy production and metabolic pathways in the pathogenesis and pathophysiology of demyelinating diseases.

The myelin sheath is a plasma membrane extension that lines nerve fibers to protect, support and insulate neurons. The myelination of axons in vertebrates enables fast, saltatory impulse propagation, and this process relies on organelles, especially on mitochondria to supply energy. Approximately 99% of mitochondrial proteins are encoded in the nucleus. Since mitochondria play a central role in the energy production and metabolic pathways, which are essential for myelinogenesis, studying these nucleus-encoded genes (nMGs) may provide new insights into the roles of energy metabolism in demyelinating diseases. In this work, a multiomics-based approach was employed to 1) construct a 1,740 human nMG subset with mitochondrial localization evidence obtained from the Integrated Mitochondrial Protein Index (IMPI) and MitoCarta databases, 2) conduct an evolutionary genomics analysis across mouse, rat, monkey, chimp, and human models, 3) examine dysmyelination phenotype-related genes (nMG subset genes with oligodendrocyte- ​and myelin-related ​phenotypes, OMP-nMGs) in MGI mouse lines and human patients, 4) determine the expression discrepancy of OMP-nMGs in brain tissues of cuprizone-treated mice, multiple sclerosis patients, and normal controls, and 5) conduct literature data mining to explore OMP-nMG-associated disease impacts. By contrasting OMP-nMGs with other genes, OMP-nMGs were found to be more ubiquitously expressed (59.1% vs. 16.1%), disease-associated (67.3% vs. 20.2%), and evolutionarily conserved within the human populations. Our multiomics-based analysis identified 110 OMP-nMGs implicated in energy production and lipid and glycan biosynthesis in the pathogenesis and pathophysiology of demyelinating disorders. Future targeted characterization of OMP-nMGs in abnormal myelination conditions may allow the discovery of novel nMG mediated mechanisms underlying myelinogenesis and related diseases.

The complete mitochondrial genome of Sesarmops sinensis reveals gene rearrangements and phylogenetic relationships in Brachyura.

Mitochondrial genome (mitogenome) is very important to understand molecular evolution and phylogenetics. Herein, in this study, the complete mitogenome of Sesarmops sinensis was reported. The mitogenome was 15,905 bp in size, and contained 13 protein-coding genes (PCGs), two ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes, and a control region (CR). The AT skew and the GC skew are both negative in the mitogenomes of S. sinensis. The nucleotide composition of the S. sinensis mitogenome was also biased toward A + T nucleotides (75.7%). All tRNA genes displayed a typical mitochondrial tRNA cloverleaf structure, except for the trnS1 gene, which lacked a dihydroxyuridine arm. S. sinensis exhibits a novel rearrangement compared with the Pancrustacean ground pattern and other Brachyura species. Based on the 13 PCGs, the phylogenetic analysis showed that S. sinensis and Sesarma neglectum were clustered on one branch with high nodal support values, indicating that S. sinensis and S. neglectum have a sister group relationship. The group (S. sinensis + S. neglectum) was sister to (Parasesarmops tripectinis + Metopaulias depressus), suggesting that S. sinensis belongs to Grapsoidea, Sesarmidae. Phylogenetic trees based on amino acid sequences and nucleotide sequences of mitochondrial 13 PCGs using BI and ML respectively indicate that section Eubrachyura consists of four groups clearly. The resulting phylogeny supports the establishment of a separate subsection Potamoida. These four groups correspond to four subsections of Raninoida, Heterotremata, Potamoida, and Thoracotremata.

The Alterations in Mitochondrial DNA Copy Number and Nuclear-Encoded Mitochondrial Genes in Rat Brain Structures after Cocaine Self-Administration.

The repeated intake of cocaine evokes oxidative stress that is present even during drug withdrawal. Recent studies demonstrate that cocaine-induced oxidative and/or endoplasmic reticulum stress can affect mitochondrial function and dynamics as well as the expression of mitochondrial and nuclear genes. These alterations in mitochondrial function may determine synaptic and behavioral plasticity. Mitochondria and mitochondrial DNA (mtDNA) seem to play an important role in the initiation of drug addiction. We used a microarray approach to investigate the expression patterns of nuclear-encoded genes relevant for mitochondrial functions and quantitative real-time PCR assays to determine the numbers of copies of mtDNA and of mRNAs corresponding to two mitochondrial proteins in the prefrontal cortex and hippocampus of rats during early cocaine abstinence. We found a significant elevation in the copy number of mtDNA and concomitant increased expression of mitochondrial genes. Moreover, microarray analysis revealed changes in the transcription of nuclear genes engaged in mtDNA replication, nucleoid formation, the oxidative phosphorylation pathway, and mitochondrial fission and fusion. Finally, we observed the upregulation of endoplasmic reticulum stress-induced genes. Cocaine self-administration influences the expression of both nuclear and mitochondrial genes as well as mtDNA replication. To determine whether these alterations serve as compensatory mechanisms to help maintain normal level of ATP production, further studies are necessary.

Macrophages Promote Oxidative Metabolism To Drive Nitric Oxide Generation in Response to Trypanosoma cruzi.

Trypanosoma cruzi is the causative agent of chronic chagasic cardiomyopathy. Why macrophages (mφs), the early responders to infection, fail to achieve parasite clearance is not known. Mouse (RAW 264.7) and human (THP-1 and primary) mφs were infected for 3 h and 18 h with T. cruzi TcI isolates, SylvioX10/4 (SYL, virulent) and TCC (nonpathogenic), which represent mφ stimulation and infection states, respectively. Mφs incubated with lipopolysaccharide and gamma interferon (LPS/IFN-γ) and with interleukin-4 (IL-4) were used as controls. We monitored the cytokine profile (using enzyme-linked immunosorbent assay [ELISA]), reactive oxygen species (ROS; fluorescent probes), nitric oxide (·NO; Griess assay), and metabolic state using a custom-designed mitoxosome array and Seahorse XF24 Analyzer. LPS/IFN-γ treatment of mφs elicited a potent increase in production of tumor necrosis alpha (TNF-α) at 3 h and of ROS and ·NO by 18 h. Upon SYL infection, murine mφs elicited an inflammatory cytokine profile (TNF-α ≫ TGF-ß + IL-10) and low levels of ·NO and ROS production. LPS/IFN-γ treatment resulted in the inhibition of oxidative metabolism at the gene expression and functional levels and a switch to the glycolytic pathway in mφs, while IL-4-treated mφs utilized oxidative metabolism to meet energy demands. SYL infection resulted in an intermediate functional metabolic state with increased mitoxosome gene expression and glycolysis, and IFN-γ addition shut down the oxidative metabolism in SYL-infected mφs. Further, TCC- and SYL-stimulated mφs exhibited similar levels of cell proliferation and production of TNF-α and ROS, while TCC-stimulated mφs exhibited up to 2-fold-higher levels of oxidative metabolism and ·NO production than SYL-infected mφs. Inhibiting ATP-coupled O2 consumption suppressed the ·NO generation in SYL-infected mφs. Mitochondrial oxygen consumption constitutes a mechanism for stimulating ·NO production in mφs during T. cruzi infection. Enhancing the oxidative metabolism provides an opportunity for increased ·NO production and pathogen clearance by mφs to limit disease progression.

Dos hermanas con distrofia macular causada por la mutación 3243A>G del ADN mitocondrial / Two sisters with macular dystrophy caused by the 3243A>G mitochondrial DNA mutation

CASO CLÍNICO: Dos hermanas de 54 y 60 años, con antecedentes de diabetes y sordera, consultaron por disminución de la agudeza visual (AV). En la funduscopia se observaban áreas parcheadas de atrofia coriorretiniana con disposición anular alrededor de la fóvea. El estudio genético identificó la mutación heteroplásmica 3243A>G en el ADN mitocondrial, compatible con el síndrome Maternally Inherited Diabetes and Deafness (MIDD) o enfermedad de Ballinger-Wallace. Discusión: El hallazgo de tales alteraciones maculares características, especialmente si se acompaña de diabetes mellitus y sordera, nos debe indicar la realización de un cribado del genoma mitocondrial para identificar este inusual síndrome

CASE REPORT: Two sisters of 54 and 60 years old, with a history of diabetes and deafness, consulted for decreased visual acuity (VA). Funduscopic examination revealed patchy areas of chorioretinal atrophy with annular arrangement around the fovea. Genetic study identified the heteroplasmic mutation 3243A>G in mitochondrial DNA, which supports syndrome maternally inherited diabetes and deafness (MIDD) or Ballinger-Wallace disease. DISCUSSION: The finding of such macular disorders, especially in the presence of diabetes mellitus and deafness, should suggest the performing of a mitochondrial genome screening to identify this unusual syndrome

Complete mitochondrial DNA genome of tetraploid Carassius auratus gibelio.

The complete mitochondrial genome was sequenced from the tetraploid Carassius auratus gibelio in this study. The genome sequence was 16,576 bp in length. The mitochondrial genome contains 13 protein-coding genes, 2 ribosomal RNAs, 22 transfer RNAs, and 2 non-coding regions (control region and origin of light-strand replication). All genes were encoded on the heavy strain except for ND6 and eight tRNA genes. The overall base composition is 31.61% A, 25.81% T, 26.62% G, 15.96% C, with an A+T bias of 57.42%. The complete mitogenome data provides useful genetic markers for the studies on the molecular identification, population genetics, phylogenetic analysis and conservation genetics.

Complete mitochondrial genome of the hardnose shark Carcharhinus macloti (Carcharhiniformes: Carcharhinidae).

The complete mitochondrial genome of Carcharhinus macloti was determined in this study. It is 16,701 bp in length and contains 37 genes with the typical gene order and transcriptional orientation in vertebrates. A total of 29 bp overlaps and 29 bp short intergenic spaces located in 22 gene junctions. The overall base composition is 31.6% A, 26.2% C, 13.0% G and 29.2% T. Two start codons (ATG and GTG) and three stop codons (AGG, TAG and TAA/T) were found in 13 protein-coding genes. The length of 22 tRNA genes ranged from 66 bp (tRNA-Ser2) to 75 bp (tRNA-Leu1). The tRNA-Ser2 (GCU) lacks the dihydrouridine arm by a simple loop and can not be folded into the typical cloverleaf structure. The control region is 1066 bp in length with high A+T content (68.2%).

Complete mitochondrial genome of the pink clownfish Amphiprion perideraion (Pisces: Perciformes, Pomacentridae).

In this study the complete mitochondrial (mt) genome of the pink clownfish Amphiprion perideraion was obtained by using eight consensus primer pairs with a long PCR technique. The circular mtDNA molecule was 16,579 bp in size and the overall nucleotide composition of the H-strand was 29.37% A, 25.50% T, 15.68% G and 29.45% C, with an A + T bias. The complete mitogenome contained 13 protein-coding genes, 2 rRNAs, 22 tRNAs and a control region, and the gene order was typical of vertebrate mitogenomes. The complete mitochondrial genome of A. perideraion is a representative of the subgenus Phalerebus for mitogenomes database of anemonefishes, which can be used to unveil taxonomic problems and phylogenetic relationships in Amphiprioninae.

Complete mitochondrial genome of the invasive brown alga Sargassum muticum (Sargassaceae, Phaeophyceae).

Sargassum muticum (Yendo) Fensholt is an invasive canopy-forming brown alga, expanding its presence from Northeast Asia to North America and Europe. The complete mitochondrial genome of S. muticum is characterized as a circular molecule of 34,720 bp. The overall AT content of S. muticum mitogenome is 63.41%. This mitogenome contains 65 genes typically found in brown algae, including 3 ribosomal RNA genes, 25 transfer RNA genes, 35 protein-coding genes, and 2 conserved open reading frames (ORFs). The gene order of mitogenome for S. muticum is identical to that for Sargassum horneri, Fucus vesiculosus and Desmarestia viridis. Phylogenetic analyses based on 35 protein-coding genes reveal that S. muticum has a close evolutionary relationship with S. horneri and a distant relationship with Dictyota dichotoma, supporting current taxonomic systems. The present investigation provides new molecular data for studies of S. muticum population diversity as well as comparative genomics in the Phaeophyceae.

The complete mitochondrial genome of the hybrid of Siniperca scherzeri (♀) × Siniperca chuatsi (♂).

In the present study, the complete mitogenome of the hybrid of Siniperca scherzeri (♀) × Siniperca chuatsi (♂) is determined to be 16,504 bp long and showed a typical vertebrate pattern with 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and a control region. The base composition of heave strand in descending order is C (29.61%), A (28.31%), T (25.61%) and G (16.47%), with a slight AT bias of 53.92%. All the protein-coding genes are initiated by typical ATG codon, except for COX1 gene with the initiation codon GTG. Nine genes end with the complete stop codon TAA or TAG, while the COX1, COX2, ND4 and CYTB genes terminate with an incomplete stop codon T. The complete mitogenome of the hybrid of S. scherzeri (♀) × S. chuatsi (♂) could provide an important data set for the study in mitochondrial inheritance mechanism.

Complete mitochondrial genome of the Japanese pine sawyer, Monochamus alternatus (Coleoptera: Cerambycidae).

We determined the complete mitochondrial genome of the Japanese pine sawyer Monochamus alternatus Hope (Coleoptera: Cerambycidae), which is a major forest pest in Asia. The genome is 15,874 bp in length containing 37 typical animal mitochondrial genes and one non-coding A+T-rich region. Its gene content and order are typical of other coleopteran mitochondrial genomes described to date. All protein-coding genes (PCGs) are initiated by ATN codons. Eight PCGs use complete stop codons TAG or TAA, whereas other PCGs end with a single T. All tRNA genes show typical secondary cloverleaf structures except for tRNA(Ser(AGN)), which lacks the dihydrouridine (DHU) arm. The large non-coding A+T-rich region of 1249 bp contains a 14 bp-long poly-T stretch and two microsatellite-like (AT)(TA)7 and (TA)8 elements.

The complete mitochondrial genome of Channa marulius (Perciformes: Channidae: Channa).

The traditional polymerase chain reaction method was employed to obtain the complete mitochondrial genome of Channa marulius from Pakistan. The mitogenome was determined to be 16,569 bp in length. It contains 13 protein-coding genes, 2 rRNAs and 22 tRNAs. This is the first report on the complete mitogenome sequence of C. marulius.

Complete mitochondrial genome sequence of golden pompano Trachinotus ovatus.

The complete mitochondrial genome of Trachinotus ovatus was determined by the polymerase chain reaction (PCR). The mitogenome is 16,564 bp long and has the typical vertebrate mitochondrial gene arrangement, including 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes and one control region. The overall base composition of mitogenome is estimated to be 29.0% for A, 28.9% for C, 26.2% for T, 15.9% for G, respectively, with a high A + T content (55.2%). With the exception of ND6 and eight tRNA genes, all other mitochondrial genes are encoded on the heavy strand. The control region contains a dinucleotide repeat motif, (AT)5. This mitogenome sequence would play an important role in population genetics and the molecular taxonomy of T. ovatus.

Complete mitochondrial genome of the blacktip reef shark Carcharhinus melanopterus (Carcharhiniformes: Carcharhinidae).

The complete mitochondrial genome of the blacktip reef shark Carcharhinus melanopterus is determined for the first time in this study. The gene composition and order in the mitogenome of C. melanopterus is identical to most vertebrates. The overall base composition is 31.3% A, 25.3% C, 13.3% G and 30.1% T. There are 29 bp overlaps and 21 bp short intergenic spaces in the mitogenome. Two start codons and three stop codons were found in protein-coding genes. The dihydrouridine arm of tRNA-Ser2 was replaced by a simple loop and the other tRNAs could be folded into the typical cloverleaf structure. The termination associated sequence (TAS) and the conserved sequence blocks (CSB1-3) are found in the control region.

Complete sequence and gene organization of the mitochondrial genome of Podocnemis unifilis (Pleurodira: Podocnemididae).

The mitochondrial genome of Podocnemis unifilis (Pleurodira: Podocnemididae) is 16,493 bp in length, which contains 13 protein-coding genes, 2 ribosomal RNAs, 22 transfer RNAs, and a control region. The A+T content of the overall base composition of H-strand is 61.7% (T: 27.7%, C: 25.5%, A: 34.0%, G: 12.8%). ATP6, ATP8, CO3, ND4-6 and Cyt b genes begin with ATG as start codon, ND1, ND2 and ND4L begin with ATT, CO1 starts with GTG, CO2 starts with ATA, ND3 starts with ATC. ATP6, CO2, ND4L and ND5 genes are terminated with TAA as stop codon, ND1, ND2, ND3, ND6 and CO1 end with TAG, and the other four protein-coding genes end with an incomplete stop codon (a single stop nucleotide T or TA). A long unit repeat region is found in the control region.