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  1. Fulltext Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant
    Garg A, Keng WT, Chen Z, Sathe AA, Xing C, Kailasam PD, et al.
    J Clin Invest, 2022 Dec 01;132(23).
    PMID: 36282599 DOI: 10.1172/JCI156864
    Multiple genetic loci have been reported for progeroid syndromes. However, the molecular defects in some extremely rare forms of progeria have yet to be elucidated. Here, we report a 21-year-old man of Chinese ancestry who has an autosomal recessive form of progeria, characterized by severe dwarfism, mandibular hypoplasia, hyperopia, and partial lipodystrophy. Analyses of exome sequencing data from the entire family revealed only 1 rare homozygous missense variant (c.86C>T; p.Pro29Leu) in TOMM7 in the proband, while the parents and 2 unaffected siblings were heterozygous for the variant. TOMM7, a nuclear gene, encodes a translocase in the outer mitochondrial membrane. The TOMM complex makes up the outer membrane pore, which is responsible for importing many preproteins into the mitochondria. A proteomic comparison of mitochondria from control and proband-derived cultured fibroblasts revealed an increase in abundance of several proteins involved in oxidative phosphorylation, as well as a reduction in abundance of proteins involved in phospholipid metabolism. We also observed elevated basal and maximal oxygen consumption rates in the fibroblasts from the proband as compared with control fibroblasts. We concluded that altered mitochondrial protein import due to biallelic loss-of-function TOMM7 can cause severe growth retardation and progeroid features.
    Matched MeSH terms: Mitochondrial Proteins/genetics
  2. Is Malaysia's banded langur, Presbytis femoralis femoralis, actually Presbytis neglectus neglectus? Taxonomic revision with new insights on the radiation history of the Presbytis species group in Southeast Asia
    Abdul-Latiff MAB, Baharuddin H, Abdul-Patah P, Md-Zain BM
    Primates, 2019 Jan;60(1):63-79.
    PMID: 30471014 DOI: 10.1007/s10329-018-0699-y
    The disjunct distribution of Presbytis femoralis subspecies across Sumatra (P. f. percura), southern (P. f. femoralis) and northern (P. f. robinsoni) Peninsular Malaysia marks the unique vicariance events in the Sunda Shelf. However, the taxonomic positions and evolutionary history of P. f. femoralis are unresolved after decades of research. To elucidate this evolutionary history, we analyzed 501 base pairs of the mitochondrial HVSI gene from 25 individuals representing Malaysia's banded langur, with the addition of 29 sequences of Asian Presbytis from Genbank. Our results revealed closer affinity of P. f. femoralis to P. m. mitrata and P. m. sumatrana while maintaining the monophyletic state of P. f. femoralis as compared to P. f. robinsoni. Two central theses were inferred from the results; (1) P. f. femoralis does not belong in the same species classification as P. f. robinsoni, and (2) P. f. femoralis is the basal lineage of the Presbytis in Peninsular Malaysia. Proving the first hypothesis through genetic analysis, we reassigned P. f. femoralis of Malaysia to Presbytis neglectus (Schlegel's banded langur) (Schlegel in Revue Methodique, Museum d'Histoire Naturelle des Pays-Bas 7:1, 1876) following the International Code of Zoological Nomenclature (article 23.3). The ancestors of P. neglectus are hypothesized to have reached southern Peninsular Malaysia during the Pleistocene and survived in refugium along the western coast. Consequently, they radiated upward, forming P. f. robinsoni and P. siamensis resulting in the highly allopatric distribution in Peninsular Malaysia. This study has successfully resolved the taxonomic position of P. neglectus in Peninsular Malaysia while providing an alternative biogeographic theory for the Asian Presbytis.
    Matched MeSH terms: Mitochondrial Proteins/genetics*
  3. Fulltext Complete Mitochondrial Genome of Three Bactrocera Fruit Flies of Subgenus Bactrocera (Diptera: Tephritidae) and Their Phylogenetic Implications
    Yong HS, Song SL, Lim PE, Eamsobhana P, Suana IW
    PLoS One, 2016;11(2):e0148201.
    PMID: 26840430 DOI: 10.1371/journal.pone.0148201
    Bactrocera latifrons is a serious pest of solanaceous fruits and Bactrocera umbrosa is a pest of Artocarpus fruits, while Bactrocera melastomatos infests the fruit of Melastomataceae. They are members of the subgenus Bactrocera. We report here the complete mitochondrial genome of these fruit flies determined by next-generation sequencing and their phylogeny with other taxa of the subgenus Bactrocera. The whole mitogenomes of these three species possessed 37 genes namely, 13 protein-coding genes (PCGs), 2 rRNA and 22 tRNA genes. The mitogenome of B. latifrons (15,977 bp) was longer than those of B. melastomatos (15,954 bp) and B. umbrosa (15,898 bp). This difference can be attributed to the size of the intergenic spacers (283 bp in B. latifrons, 261 bp in B. melastomatos, and 211 bp in B. umbrosa). Most of the PCGs in the three species have an identical start codon, except for atp8 (adenosine triphosphate synthase protein 8), which had an ATG instead of GTG in B. umbrosa, whilst the nad3 (NADH dehydrogenase subunit 3) and nad6 (NADH dehydrogenase subunit 6) genes were characterized by an ATC instead of ATT in B. melastomatos. The three species had identical stop codon for the respective PCGs. In B. latifrons and B. melastomatos, the TΨC (thymidine-pseudouridine-cytidine)-loop was absent in trnF (phenylalanine) and DHU (dihydrouracil)-loop was absent in trnS1 (serine S1). In B. umbrosa, trnN (asparagine), trnC (cysteine) and trnF lacked the TψC-loop, while trnS1 lacked the DHU-stem. Molecular phylogeny based on 13 PCGs was in general concordant with 15 mitochondrial genes (13 PCGs and 2 rRNA genes), with B. latifrons and B. umbrosa forming a sister group basal to the other species of the subgenus Bactrocera which was monophyletic. The whole mitogenomes will serve as a useful dataset for studying the genetics, systematics and phylogenetic relationships of the many species of Bactrocera genus in particular, and tephritid fruit flies in general.
    Matched MeSH terms: Mitochondrial Proteins/genetics*
  4. Fulltext AarF Domain Containing Kinase 3 (ADCK3) Mutant Cells Display Signs of Oxidative Stress, Defects in Mitochondrial Homeostasis and Lysosomal Accumulation
    Cullen JK, Abdul Murad N, Yeo A, McKenzie M, Ward M, Chong KL, et al.
    PLoS One, 2016;11(2):e0148213.
    PMID: 26866375 DOI: 10.1371/journal.pone.0148213
    Autosomal recessive ataxias are a clinically diverse group of syndromes that in some cases are caused by mutations in genes with roles in the DNA damage response, transcriptional regulation or mitochondrial function. One of these ataxias, known as Autosomal Recessive Cerebellar Ataxia Type-2 (ARCA-2, also known as SCAR9/COQ10D4; OMIM: #612016), arises due to mutations in the ADCK3 gene. The product of this gene (ADCK3) is an atypical kinase that is thought to play a regulatory role in coenzyme Q10 (CoQ10) biosynthesis. Although much work has been performed on the S. cerevisiae orthologue of ADCK3, the cellular and biochemical role of its mammalian counterpart, and why mutations in this gene lead to human disease is poorly understood. Here, we demonstrate that ADCK3 localises to mitochondrial cristae and is targeted to this organelle via the presence of an N-terminal localisation signal. Consistent with a role in CoQ10 biosynthesis, ADCK3 deficiency decreased cellular CoQ10 content. In addition, endogenous ADCK3 was found to associate in vitro with recombinant Coq3, Coq5, Coq7 and Coq9, components of the CoQ10 biosynthetic machinery. Furthermore, cell lines derived from ARCA-2 patients display signs of oxidative stress, defects in mitochondrial homeostasis and increases in lysosomal content. Together, these data shed light on the possible molecular role of ADCK3 and provide insight into the cellular pathways affected in ARCA-2 patients.
    Matched MeSH terms: Mitochondrial Proteins/genetics
  5. Indigenous Dirofilaria immitis in Bangladesh
    Fuehrer HP, Treiber M, Silbermayr K, Baumann TA, Swoboda P, Joachim A, et al.
    Parasitol Res, 2013 Jun;112(6):2393-5.
    PMID: 23358737 DOI: 10.1007/s00436-013-3311-9
    Dirofilaria immitis is a parasite of domestic and wild canids and felids in tropical, subtropical and temperate regions throughout the world. The canine heartworm (D. immitis) is the causative agent of canine and feline cardiopulmonary dirofilariasis. This parasite is known to cause a zoonotic disease, namely human pulmonary dirofilariasis. D. immitis is known to be endemic in several South and Southeast Asian countries (e.g. India and Malaysia), but there has previously been no information about the presence of this pathogen in Bangladesh. We present a case of canine dirofilariasis caused by D. immitis in rural southeastern Bangladesh. A male filaroid nematode (95 mm in length and 1.94 mm in width) was identified in the heart of a dog. Species classification was performed by microscopy and molecular tools. Sequence analysis revealed a 100 % identity within the mitochondrial cytochrome c oxidase I (CO1) gene to two Chinese and one Australian D. immitis samples. Usually, dogs stay outside overnight with a high risk to get infected with D. immitis via nocturnal mosquito vectors, which may lead to high prevalences of this pathogen in the canine population and thus increase the risk of human infections with this neglected parasitic disease.
    Matched MeSH terms: Mitochondrial Proteins/genetics
  6. Uncoupling protein 2 promoter polymorphism -866G/A, central adiposity, and metabolic syndrome in Asians
    Shen H, Qi L, Tai ES, Chew SK, Tan CE, Ordovas JM
    Obesity (Silver Spring), 2006 Apr;14(4):656-61.
    PMID: 16741267
    A polymorphism in the promoter region of uncoupling protein 2 gene -866G/A has been associated with its expression levels in adipose tissue, the risk of obesity, and metabolic abnormalities. Our purpose was to examine the associations of -866G/A with body fat and the risk of metabolic syndrome in a random sample of 4018 Asians (1858 men and 2160 women) from three ethnic groups (Chinese, Malay, and Indian). The minor allele frequency of -866G/A polymorphism in South Asians was similar to that in whites. After adjustment for covariates including age, cigarette smoking, and physical activity, the -866A/A genotype was associated with higher waist-to-hip ratio as compared with the wild-type genotype in Chinese and Indian men (p = 0.018 and p = 0.046, respectively). Moreover, Indian men with -866A/A genotype had a significantly increased risk of metabolic syndrome as compared with those homozygous for the wild-type (odds ratio, 2.66; 95% confidence interval, 1.21 to 5.88; p = 0.015). Such a risk was mainly caused by the excess presence of hypertriglyceridemia and central obesity. Our findings indicate that the uncoupling protein 2 gene -866G/A polymorphism may increase the risks of central obesity and metabolic syndrome, with greater effects on Asian men.
    Matched MeSH terms: Mitochondrial Proteins/genetics*
  7. X-linked Charcot-Marie-Tooth disease predominates in a cohort of multiethnic Malaysian patients
    Shahrizaila N, Samulong S, Tey S, Suan LC, Meng LK, Goh KJ, et al.
    Muscle Nerve, 2014 Feb;49(2):198-201.
    PMID: 23649551 DOI: 10.1002/mus.23892
    Data regarding Charcot-Marie-Tooth disease is lacking in Southeast Asian populations. We investigated the frequency of the common genetic mutations in a multiethnic Malaysian cohort.
    Matched MeSH terms: Mitochondrial Proteins/genetics
  8. Mutations in mitochondrial complex I assembly factor NDUFAF3 cause Leigh syndrome
    Baertling F, Sánchez-Caballero L, Timal S, van den Brand MA, Ngu LH, Distelmaier F, et al.
    Mol Genet Metab, 2017 03;120(3):243-246.
    PMID: 27986404 DOI: 10.1016/j.ymgme.2016.12.005
    NDUFAF3 is an assembly factor of mitochondrial respiratory chain complex I. Variants in NDUFAF3 have been identified as a cause of severe multisystem mitochondrial disease. In a patient presenting with Leigh syndrome, which has hitherto not been described as a clinical feature of NDUFAF3 deficiency, we identified a novel homozygous variant and confirmed its pathogenicity in patient fibroblasts studies. Furthermore, we present an analysis of complex I assembly routes representative of each functional module and, thereby, link NDUFAF3 to a specific step in complex I assembly. Therefore, our report expands the phenotype of NDUFAF3 deficiency and further characterizes the role of NDUFAF3 in complex I biogenesis.
    Matched MeSH terms: Mitochondrial Proteins/genetics*
  9. Lauric acid alleviates insulin resistance by improving mitochondrial biogenesis in THP-1 macrophages
    Tham YY, Choo QC, Muhammad TST, Chew CH
    Mol Biol Rep, 2020 Dec;47(12):9595-9607.
    PMID: 33259010 DOI: 10.1007/s11033-020-06019-9
    Mitochondrial dysfunction plays a crucial role in the central pathogenesis of insulin resistance and type 2 diabetes mellitus. Macrophages play important roles in the pathogenesis of insulin resistance. Lauric acid is a 12-carbon medium chain fatty acid (MCFA) found abundantly in coconut oil or palm kernel oil and it comes with multiple beneficial effects. This research objective was to uncover the effects of the lauric acid on glucose uptake, mitochondrial function and mitochondrial biogenesis in insulin-resistant macrophages. THP-1 monocytes were differentiated into macrophages and induce insulin resistance, before they were treated with increasing doses of lauric acid (5 μM, 10 μM, 20 μM, and 50 μM). Glucose uptake assay, cellular ROS and ATP production assays, mitochondrial content and membrane potential assay were carried out to analyse the effects of lauric acid on insulin resistance and mitochondrial biogenesis in the macrophages. Quantitative RT-PCR (qRT-PCR) and western blot analysis were also performed to determine the expression of the key regulators. Insulin-resistant macrophages showed lower glucose uptake, GLUT-1 and GLUT-3 expression, and increased hallmarks of mitochondrial dysfunction. Interestingly, lauric acid treatment upregulated glucose uptake, GLUT-1 and GLUT-3 expressions. The treatment also restored the mitochondrial biogenesis in the insulin-resistant macrophages by improving ATP production, oxygen consumption, mitochondrial content and potential, while it promoted the expression of mitochondrial biogenesis regulator genes such as TFAM, PGC-1α and PPAR-γ. We show here that lauric acid has the potential to improve insulin sensitivity and mitochondrial dysregulation in insulin-resistant macrophages.
    Matched MeSH terms: Mitochondrial Proteins/genetics
  10. Phylogeography of Tetrancistrum nebulosi (Monogenea, Dactylogyridae) on the host of mottled spinefoot (Siganus fuscescens) in the South China Sea, inferred from mitochondrial COI and ND2 genes
    Wang M, Yan S, Brown CL, Shaharom-Harrison F, Shi SF, Yang TB
    Mitochondrial DNA A DNA Mapp Seq Anal, 2016 11;27(6):3865-3875.
    PMID: 25319302
    To examine the phylogeographical pattern of Tetrancistrum nebulosi (Monogenea, Dactylogyridae) in the South China Sea, fragments of mitochondrial cytochrome c oxidase subunit I and NADH dehydrogenase subunit 2 genes were obtained for 220 individuals collected from 8 localities along the southeast coast of China and 1 locality in Terengganu, Malaysia. Based on these two genes, two and three distinct clades with geographic signals were revealed on the phylogenetic trees respectively. The divergence between these clades was estimated to occur in the late Pleistocene. Analysis of molecular variance and pairwise FSTsuggested a high rate of gene flow among individuals sampled from the Chinese coast, but with obvious genetic differentiation from the Malaysian population. Mismatch distribution and neutrality tests indicated that the T. nebulosi population experienced expansion in Pleistocene low sea level periods. Vicariance was considered to account for the genetic divergence between Chinese and Malaysian populations, while sea level fluctuations and mainland-island connections during glacial cycles were associated with the slight genetic divergence between the populations along the mainland coast of China and those off Sanya. On the contrary, oceanographic circulations and host migration could lead to genetic homogeneity of populations distributed along the mainland coast of China.
    Matched MeSH terms: Mitochondrial Proteins/genetics
  11. The complete mitogenome of the minute mudskipper, Periophthalmus minutus Eggert, 1935 (Perciformes: Gobiidae: Oxudercinae)
    Gan HM, Tan MH, Lee YP, Hammer MP, Austin CM
    Mitochondrial DNA A DNA Mapp Seq Anal, 2016 11;27(6):4187-4188.
    PMID: 25600740
    The mitogenome of an Australian sample of the mudskipper, Periophthalmus minutus, was recovered from partial sequencing using the MiSeq sequencer. This mudskipper has a mitogenome of 16,506 base pairs (55% A + T content) made up of two ribosomal subunit genes, 13 protein-coding genes, 22 transfer RNAs, and a 838 bp non-coding AT-rich region. This is the first sequenced mitogenome for the genus Periophthalmus and the fifth for the subfamily Oxudercinae.
    Matched MeSH terms: Mitochondrial Proteins/genetics*
  12. A multi-locus approach resolves the phylogenetic relationships of the Simulium asakoae and Simulium ceylonicum species groups in Malaysia: evidence for distinct evolutionary lineages
    Low VL, Takaoka H, Adler PH, Ya'cob Z, Norma-Rashid Y, Chen CD, et al.
    Med Vet Entomol, 2015 Sep;29(3):330-7.
    PMID: 25968459 DOI: 10.1111/mve.12120
    A multi-locus approach was used to examine the DNA sequences of 10 nominal species of blackfly in the Simulium subgenus Gomphostilbia (Diptera: Simuliidae) in Malaysia. Molecular data were acquired from partial DNA sequences of the mitochondria-encoded cytochrome c oxidase subunit I (COI), 12S rRNA and 16S rRNA genes, and the nuclear-encoded 18S rRNA and 28S rRNA genes. No single gene, nor the concatenated gene set, resolved all species or all relationships. However, all morphologically established species were supported by at least one gene. The multi-locus sequence analysis revealed two distinct evolutionary lineages, conforming to the morphotaxonomically recognized Simulium asakoae and Simulium ceylonicum species groups.
    Matched MeSH terms: Mitochondrial Proteins/genetics
  13. Mitochondrial Cytochrome Oxidase I Gene Sequence Analysis of Aedes Albopictus in Malaysia
    Ismail NA, Dom NC, Ismail R, Ahmad AH, Zaki A, Camalxaman SN
    J Am Mosq Control Assoc, 2015 Dec;31(4):305-12.
    PMID: 26675451 DOI: 10.2987/moco-31-04-305-312.1
    A study was conducted to establish polymorphic variation of the mitochondrial DNA encoding the cytochrome oxidase subunit 1 (CO1) gene in Aedes albopictus isolated from 2 hot spot dengue-infested areas in the Subang Jaya District, Malaysia. A phylogenetic analysis was performed with the use of sequences obtained from USJ6 and Taman Subang Mas (TSM). Comparison of the local CO1 sequences with a laboratory strain (USM), alongside reference strains derived from the GenBank database revealed low genetic variation in terms of nucleotide differences and haplotype diversity. Four methods were used to construct a phylogenetic tree and illustrate the genetic relationship of the 37 Ae. albopictus populations based on the CO1 sequences, namely neighbor-joining (NJ), maximum parsimony (MP), maximum likelihood (ML), and Bayesian method, which revealed a distinct relationship between isolates from USJ6 and TSM. Our findings provide new information regarding the genetic diversity among morphologically similar Ae. albopictus, which has not been reported to date.
    Matched MeSH terms: Mitochondrial Proteins/genetics
  14. Uncoupling protein 2 gene (UCP2) 45-bp I/D polymorphism is associated with adiposity among Malaysian women
    Say YH, Ban ZL, Arumugam Y, Kaur T, Tan ML, Chia PP, et al.
    J Biosci, 2014 Dec;39(5):867-75.
    PMID: 25431415
    This study investigated the association of Uncoupling Protein 2 gene (UCP2) 45-bp I/D polymorphism with obesity and adiposity in 926 Malaysian subjects (416 males;265 obese; 102/672/152 Malays/Chinese/Indians). The overall minor allele frequency (MAF) was 0.14, while MAFs according to Malay/Chinese/Indian were 0.17/0.12/0.21. The polymorphism was associated with ethnicity, obesity and overall adiposity (total body fat percentage, TBF), but not gender and central adiposity (waist-hip ratio, WHR). Gender- and ethnicity-stratified analysis revealed that within males, the polymorphism was not associated with ethnicity and anthropometric classes. However, within females, significantly more Indians, obese and those with high TBF carried I allele. Logistic regression analysis among females further showed the polymorphism was associated with obesity and overall adiposity; however, when adjusted for age and ethnicity, this association was abolished for obesity but remained significant for overall adiposity [Odds Ratio (OR) for ID genotype = 2.02 (CI=1.18, 3.45; p=0.01); I allele =1.81 (CI=1.15, 2.84; p=0.01)]. Indeed, covariate analysis controlling for age and ethnicity also showed that those carrying ID genotype or I allele had significantly higher TBF than the rest. In conclusion, UCP2 45-bp I/D polymorphism is associated with overall adiposity among Malaysian women.
    Matched MeSH terms: Mitochondrial Proteins/genetics*
  15. Association of UCP1 -3826A/G and UCP3 -55C/T gene polymorphisms with obesity and its related traits among multi-ethnic Malaysians
    Lee KH, Chai VY, Kanachamy SS, Say YH
    Ethn Dis, 2015;25(1):65-71.
    PMID: 25812254
    Our study investigated the association of UCP1 -3826A/G and UCP3 -55C/T single nucleotide polymorphisms (SNPs) with obesity and its related traits among multi-ethnic Malaysians.
    Matched MeSH terms: Mitochondrial Proteins/genetics*
  16. Fulltext Bi-allelic pathogenic variants in NDUFC2 cause early-onset Leigh syndrome and stalled biogenesis of complex I
    Alahmad A, Nasca A, Heidler J, Thompson K, Oláhová M, Legati A, et al.
    EMBO Mol Med, 2020 11 06;12(11):e12619.
    PMID: 32969598 DOI: 10.15252/emmm.202012619
    Leigh syndrome is a progressive neurodegenerative disorder, most commonly observed in paediatric mitochondrial disease, and is often associated with pathogenic variants in complex I structural subunits or assembly factors resulting in isolated respiratory chain complex I deficiency. Clinical heterogeneity has been reported, but key diagnostic findings are developmental regression, elevated lactate and characteristic neuroimaging abnormalities. Here, we describe three affected children from two unrelated families who presented with Leigh syndrome due to homozygous variants (c.346_*7del and c.173A>T p.His58Leu) in NDUFC2, encoding a complex I subunit. Biochemical and functional investigation of subjects' fibroblasts confirmed a severe defect in complex I activity, subunit expression and assembly. Lentiviral transduction of subjects' fibroblasts with wild-type NDUFC2 cDNA increased complex I assembly supporting the association of the identified NDUFC2 variants with mitochondrial pathology. Complexome profiling confirmed a loss of NDUFC2 and defective complex I assembly, revealing aberrant assembly intermediates suggestive of stalled biogenesis of the complex I holoenzyme and indicating a crucial role for NDUFC2 in the assembly of the membrane arm of complex I, particularly the ND2 module.
    Matched MeSH terms: Mitochondrial Proteins/genetics
  17. Ethylmalonic encephalopathy-report of two cases
    Heberle LC, Al Tawari AA, Ramadan DG, Ibrahim JK
    Brain Dev, 2006 Jun;28(5):329-31.
    PMID: 16376514
    Ethylmalonic encephalopathy is a rare metabolic disease presenting in infancy with developmental delay, acrocyanosis, petechiae, chronic diarrhea and early death. The biochemical characteristics of this autosomal recessive disease are urinary organic acid abnormalities. Recently it has been found to be caused by mutations in the ETHE1 gene, located on Ch19q13. Only about 30 patients have been reported, and we describe two additional cases. The first patient showed a typical clinical picture and biochemical abnormalities, with additional atypical clinical features. Neuroimaging studies showed extensive changes. A new homozygous mutation in exon 3 of the ETHE1 gene was found. The second patient was not investigated genetically; however besides the typical clinical picture and biochemical profile he was found to have cytochrome C oxidase deficiency.
    Matched MeSH terms: Mitochondrial Proteins/genetics
  18. Fulltext Absence of evidence is not evidence of absence: Nanopore sequencing and complete assembly of the European lobster (Homarus gammarus) mitogenome uncovers the missing nad2 and a new major gene cluster duplication
    Gan HM, Grandjean F, Jenkins TL, Austin CM
    BMC Genomics, 2019 May 03;20(1):335.
    PMID: 31053062 DOI: 10.1186/s12864-019-5704-3
    BACKGROUND: The recently published complete mitogenome of the European lobster (Homarus gammarus) that was generated using long-range PCR exhibits unusual gene composition (missing nad2) and gene rearrangements among decapod crustaceans with strong implications in crustacean phylogenetics. Such atypical mitochondrial features will benefit greatly from validation with emerging long read sequencing technologies such as Oxford Nanopore that can more accurately identify structural variation.

    RESULTS: We re-sequenced the H. gammarus mitogenome on an Oxford Nanopore Minion flowcell and performed a long-read only assembly, generating a complete mitogenome assembly for H. gammarus. In contrast to previous reporting, we found an intact mitochondrial nad2 gene in the H. gammarus mitogenome and showed that its gene organization is broadly similar to that of the American lobster (H. americanus) except for the presence of a large tandemly duplicated region with evidence of pseudogenization in one of each duplicated protein-coding genes.

    CONCLUSIONS: Using the European lobster as an example, we demonstrate the value of Oxford Nanopore long read technology in resolving problematic mitogenome assemblies. The increasing accessibility of Oxford Nanopore technology will make it an attractive and useful tool for evolutionary biologists to verify new and existing unusual mitochondrial gene rearrangements recovered using first and second generation sequencing technologies, particularly those used to make phylogenetic inferences of evolutionary scenarios.

    Matched MeSH terms: Mitochondrial Proteins/genetics*
  19. Fulltext Mitochondrial Respiration Is Reduced in Atherosclerosis, Promoting Necrotic Core Formation and Reducing Relative Fibrous Cap Thickness
    Yu EPK, Reinhold J, Yu H, Starks L, Uryga AK, Foote K, et al.
    Arterioscler Thromb Vasc Biol, 2017 12;37(12):2322-2332.
    PMID: 28970293 DOI: 10.1161/ATVBAHA.117.310042
    OBJECTIVE: Mitochondrial DNA (mtDNA) damage is present in murine and human atherosclerotic plaques. However, whether endogenous levels of mtDNA damage are sufficient to cause mitochondrial dysfunction and whether decreasing mtDNA damage and improving mitochondrial respiration affects plaque burden or composition are unclear. We examined mitochondrial respiration in human atherosclerotic plaques and whether augmenting mitochondrial respiration affects atherogenesis.

    APPROACH AND RESULTS: Human atherosclerotic plaques showed marked mitochondrial dysfunction, manifested as reduced mtDNA copy number and oxygen consumption rate in fibrous cap and core regions. Vascular smooth muscle cells derived from plaques showed impaired mitochondrial respiration, reduced complex I expression, and increased mitophagy, which was induced by oxidized low-density lipoprotein. Apolipoprotein E-deficient (ApoE-/-) mice showed decreased mtDNA integrity and mitochondrial respiration, associated with increased mitochondrial reactive oxygen species. To determine whether alleviating mtDNA damage and increasing mitochondrial respiration affects atherogenesis, we studied ApoE-/- mice overexpressing the mitochondrial helicase Twinkle (Tw+/ApoE-/-). Tw+/ApoE-/- mice showed increased mtDNA integrity, copy number, respiratory complex abundance, and respiration. Tw+/ApoE-/- mice had decreased necrotic core and increased fibrous cap areas, and Tw+/ApoE-/- bone marrow transplantation also reduced core areas. Twinkle increased vascular smooth muscle cell mtDNA integrity and respiration. Twinkle also promoted vascular smooth muscle cell proliferation and protected both vascular smooth muscle cells and macrophages from oxidative stress-induced apoptosis.

    CONCLUSIONS: Endogenous mtDNA damage in mouse and human atherosclerosis is associated with significantly reduced mitochondrial respiration. Reducing mtDNA damage and increasing mitochondrial respiration decrease necrotic core and increase fibrous cap areas independently of changes in reactive oxygen species and may be a promising therapeutic strategy in atherosclerosis.

    Matched MeSH terms: Mitochondrial Proteins/genetics
  20. LYRM7-associated mitochondrial complex III deficiency with non-cavitating leukoencephalopathy and stroke-like episodes
    Alfattal R, Alfarhan M, Algaith AM, Albash B, Elshafie RM, Alshammari A, et al.
    Am J Med Genet A, 2023 May;191(5):1401-1411.
    PMID: 36757047 DOI: 10.1002/ajmg.a.63143
    Defects of respiratory chain complex III (CIII) result in characteristic but rare mitochondrial disorders associated with distinct neuroradiological findings. The underlying molecular defects affecting mitochondrial CIII assembly factors are few and yet to be identified. LYRM7 assembly factor is required for proper CIII assembly where it acts as a chaperone for the Rieske iron-sulfur (UQCRFS1) protein in the mitochondrial matrix and stabilizing it. We present here the seventeenth individual with LYRM7-associated mitochondrial leukoencephalopathy harboring a previously reported rare pathogenic homozygous LYRM 7 variant, c.2T>C, (p.Met1?). Like previously reported individuals, our 5-year-old male proband presented with recurrent metabolic and lactic acidosis, encephalopathy, and fatigue. Further, he has additional, previously unreported features, including an acute stroke like episode with bilateral central blindness and optic neuropathy, recurrent hyperglycemia and hypertension associated with metabolic crisis. However, he has no signs of psychomotor regression. He has been stable clinically with residual left-sided reduced visual acuity and amblyopia, and no more metabolic crises for 2-year-period while on the mitochondrial cocktail. Although the reported brain MRI findings in other affected individuals are homogenous, it is slightly different in our index, revealing evidence of bilateral almost symmetric multifocal periventricular T2 hyperintensities with hyperintensities of the optic nerves, optic chiasm, and corona radiata but with no cavitation or cystic changes. This report describes new clinical and radiological findings of LYRM7-associated disease. The report also summarizes the clinical and molecular data of previously reported individuals describing the full phenotypic spectrum.
    Matched MeSH terms: Mitochondrial Proteins/genetics
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