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

Evidence for Mitochondrial UPR Gene Activation in Familial and Sporadic Alzheimer's Disease.

Mitochondrial perturbations such as oxidative stress, increased fission/fusion dysfunction, and mitophagy are consistent features of Alzheimer's disease (AD), yet the mechanisms that initiate these perturbations are unclear. One potential source for mitochondrial defects could be an imbalance in mitochondrial proteostasis. In this regard, studies indicate that a specialized mitochondrial unfolded protein response (mtUPR) is activated upon the aberrant accumulation of damaged or unfolded proteins in the mitochondrial matrix, resulting in the up-regulation of key genes involved in mitochondrial stabilization. To test whether mtUPR activation occurs in AD, we performed real-time quantitative PCR on postmortem frontal cortex samples from subjects classified as sporadic AD, familial AD linked to presenilin-1 mutations, or cognitively intact controls. Compared to controls, sporadic AD subjects exhibited a significant ~40-60% increase in expression levels of select genes activated by the mtUPR, including mitochondrial chaperones dnaja3, hspd1, and hspe1, mitochondrial proteases clpp and yme1l1, and txn2, a mitochondrial-specific oxidoreductase. Furthermore, levels of all six mtUPR genes were significantly up-regulated by ~70-90% in familial AD compared to controls, and these expression levels were significantly higher compared to sporadic AD. The increase in hspd1 (Hsp60) was validated by western blotting. These data support the concept that both sporadic and familial AD are characterized by mtUPR gene activation. Understanding the physiological consequences of this response may provide subcellular mechanistic clues to selective neuronal vulnerability or endogenous compensatory mechanisms during the progression of AD.

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 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.

The mitochondrial genome of the Vespa bicolor Fabricius (Hymenoptera: Vespidae: Vespinae).

Here, we report the first representative mitochondrial genome of the subfamily Vespinae (Hymenopterea: Vespidae) from the Vespa bicolor Fabricius (GenBank accession No. KJ735511). Nearly complete mitochondrial genome was sequenced with a length of 16,937 bp, including 13 protein-coding genes, 2 rRNA and 20 tRNA genes, as well as a portion of A+T-rich region. Two tRNA genes, i.e. trnI and trnY, were failed to sequence, which were presumed to be located within a region between A+T-rich region and trnM-trnQ-nad2. In the V. bicolor mitochondrial genome, at least three tRNA genes were rearranged. trnY was rearranged to the unsequenced region between A+T-rich region and trnM-trnQ-nad2. trnL1 was rearranged from a location between nad1 and rrnL to the upstream of nad1 gene. trnS1 and trnE were shuffled in the tRNA cluster of trnA-trnR-trnN-trnS1-trnE-trnF. Our study showed that the mitochondrial genomes between Vespinae and Polistinae shared more arrangement pattern than that between Vespinae and Eumeninae.

Mitochondrial genome of the Sichuan field mouse (Apodemus latronum).

Wood mice of the genus Apodemus are the most common small rodents in fields and broad-leaf forests in the temperate zone. In this study, we determined the complete mitochondrial genome of Apodemus latronum. It was endemic species to China, which mainly inhabited at the high land of the eastern Tibetan Plateau. The complete mitochondrial genome sequences of A. latronum was estimated to be 16,288 bases. Its organization and order were similar to that of typical vertebrate and other rodents' mitochondrial genomes, which consisting of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and 1 control region. Most protein-coding genes used ATG as the initiation codon. However, ND1, ND2 and ND5 began with ATA, whereas ND3 initiated with ATT. The termination codon also showed some degree of variation, and three types of stop codons were observed. The mitogenome sequence of A. latronum could provide helpful data to study the phylogeny of Apodemus.

The complete mitochondrial genome of Lepturichthys fimbriata (Teleostei, Balitoridae, Balitorinae).

Lepturichthys fimbriata is an endemic and an important commercial fish which distributes in the upper stream of the Yangtze River. In this study, the complete mitogenome sequence of L. fimbriata has been first sequenced by DNA sequencing based on the PCR fragments. The mitogenome, consisting of 16,567 base pairs (bp), includes 13 protein coding genes, 22 transfer RNAs, 2 ribosomal RNA genes and a non-coding control region (CR). The overall base composition of L. fimbriata is 30.4% A, 28.7% C, 16.5% G, and 24.4% T, with a relatively a slight AT bias of 54.7%. CR of 903 bp length is located between tRNA(Pro) and tRNA(Phe). The complete mitochondrial genome sequence would be useful for further studies on conservation genetics and resource management in L. fimbriata.

The complete mitochondrial genome of Saurida undosquamis (Aulopiformes: Synodontidae).

In this study, the complete mitochondrial genome (mitogenome) sequence of Saurida undosquamis has been determined by long polymerase chain reaction and primer walking methods. The complete mitochondrial genome is 16,550 bp in length and contains 37 mitochondrial genes (13 protein-coding genes, 2 ribosomal RNA (rRNA), 22 transfer RNA (tRNA)), and a control region as other bony fishes. Within the control region, we identified the termination-associated sequence domain (TAS), the central conserved sequence block domains (CSB-F, CSB-E, CSB-D, CSB-C, CSB-B and CSB-A), and the conserved sequence block domains (CSB-1, CSB-2 and CSB-3).

The complete mitochondrial genome of the Hemibarbus medius (Cypriniformes, Cyprinidae).

We present the complete mitochondrial genome of the Hemibarbus medius in this study. The mitochondrial genome is 16,611 bp in length and consists of 13 protein-coding genes, two rRNA genes, 22 tRNA genes and a control region. The nucleotide compositions of the light strand are 29.82% of A, 27.22% of C, 25.93% of T, and 17.04% of G. With the exception of ND6 and eight tRNA genes, all other mitochondrial genes are encoded on the heavy strand. All the protein-coding genes begin with an ATG initiation codon except for COXІ with GTG. Four types of termination codons revealed are TAA (ND1, COXІ, ATP8, ND4L, ND5), T (ND2, ND3, COXП, COXШ, CYTB), TA (ND4, ATP6), and TAG (ND6). Most genes are either abutted or overlapped and many features keep consistent with the other vertebrates.