bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2017‒06‒04
seven papers selected by
Gavin McStay
New York Institute of Technology

  1. Brain. 2017 Jun 01. 140(6): 1595-1610
      Although mitochondrial disorders are clinically heterogeneous, they frequently involve the central nervous system and are among the most common neurogenetic disorders. Identifying the causal genes has benefited enormously from advances in high-throughput sequencing technologies; however, once the defect is known, researchers face the challenge of deciphering the underlying disease mechanism. Here we characterize large biallelic deletions in the region encoding the ATAD3C, ATAD3B and ATAD3A genes. Although high homology complicates genomic analysis of the ATAD3 defects, they can be identified by targeted analysis of standard single nucleotide polymorphism array and whole exome sequencing data. We report deletions that generate chimeric ATAD3B/ATAD3A fusion genes in individuals from four unrelated families with fatal congenital pontocerebellar hypoplasia, whereas a case with genomic rearrangements affecting the ATAD3C/ATAD3B genes on one allele and ATAD3B/ATAD3A genes on the other displays later-onset encephalopathy with cerebellar atrophy, ataxia and dystonia. Fibroblasts from affected individuals display mitochondrial DNA abnormalities, associated with multiple indicators of altered cholesterol metabolism. Moreover, drug-induced perturbations of cholesterol homeostasis cause mitochondrial DNA disorganization in control cells, while mitochondrial DNA aggregation in the genetic cholesterol trafficking disorder Niemann-Pick type C disease further corroborates the interdependence of mitochondrial DNA organization and cholesterol. These data demonstrate the integration of mitochondria in cellular cholesterol homeostasis, in which ATAD3 plays a critical role. The dual problem of perturbed cholesterol metabolism and mitochondrial dysfunction could be widespread in neurological and neurodegenerative diseases.
    Keywords:  ATAD3; cerebellar hypoplasia; cholesterol; mitochondrial DNA; mitochondrial disease
  2. Nucleic Acids Res. 2017 May 26.
      The mechanism of mitochondrial DNA (mtDNA) replication in Saccharomyces cerevisiae is controversial. Evidence exists for double-strand break (DSB) mediated recombination-dependent replication at mitochondrial replication origin ori5 in hypersuppressive ρ- cells. However, it is not clear if this replication mode operates in ρ+ cells. To understand this, we targeted bacterial Ku (bKu), a DSB binding protein, to the mitochondria of ρ+ cells with the hypothesis that bKu would bind persistently to mtDNA DSBs, thereby preventing mtDNA replication or repair. Here, we show that mitochondrial-targeted bKu binds to ori5 and that inducible expression of bKu triggers petite formation preferentially in daughter cells. bKu expression also induces mtDNA depletion that eventually results in the formation of ρ0 cells. This data supports the idea that yeast mtDNA replication is initiated by a DSB and bKu inhibits mtDNA replication by binding to a DSB at ori5, preventing mtDNA segregation to daughter cells. Interestingly, we find that mitochondrial-targeted bKu does not decrease mtDNA content in human MCF7 cells. This finding is in agreement with the fact that human mtDNA replication, typically, is not initiated by a DSB. Therefore, this study provides evidence that DSB-mediated replication is the predominant form of mtDNA replication in ρ+ yeast cells.
  3. Mitochondrion. 2017 May 24. pii: S1567-7249(17)30142-3. [Epub ahead of print]
      Coenzyme Q10 (CoQ10) is a mitochondrial-targeted antioxidant with known neuroprotective activity. Its ocular effects when co-solubilised with α-tocopherol polyethylene glycol succinate (TPGS) were evaluated. In vitro studies confirmed that CoQ10 was significantly protective in different retinal ganglion cell (RGC) models. In vivo studies in Adult Dark Agouti (DA) rats with unilateral surgically-induced ocular hypertension (OHT) treated with either CoQ10/TPGS micelles or TPGS vehicle twice daily for three weeks were performed, following which retinal cell health was assessed in vivo using DARC (Detection of Apoptotic Retinal Cells) and post-mortem with Brn3a histological assessment on whole retinal mounts. CoQ10/TPGS showed a significant neuroprotective effect compared to control with DARC (p<0.05) and Brn3 (p<0.01). Topical CoQ10 appears an effective therapy preventing RGC apoptosis and loss in glaucoma-related models.
    Keywords:  Apoptosis; Glaucoma; Membrane biophysics; Neuroprotection; P-glycoprotein; Retinal ganglion cell
  4. Mitochondrion. 2017 May 23. pii: S1567-7249(17)30140-X. [Epub ahead of print]
      The cornea is the anterior transparent surface and the main refracting structure of the eye. Mitochondrial dysfunction and oxidative stress are implicated in the pathogenesis of inherited (e.g. Kearns Sayre Syndrome) and acquired corneal diseases (e.g. keratoconus and Fuchs endothelial corneal dystrophy). Both antioxidants and reactive oxygen species are found in the healthy cornea. There is increasing evidence of imbalance in the oxidative balance and mitochondrial function in the cornea in disease states. The cornea is vulnerable to mitochondrial dysfunction and oxidative stress due to its highly exposed position to ultraviolet radiation and high oxygen tension. The corneal endothelium is vulnerable to accumulating mitochondrial DNA (mtDNA) damage due to the post- mitotic nature of endothelial cells, yet their mitochondrial genome is continually replicating and mtDNA mutations can develop and accumulate with age. The unique physiology of the cornea predisposes this structure to oxidative damage, and there is interplay between inherited and acquired mitochondrial dysfunction, oxidative damage and a number of corneal diseases. By targeting mitochondrial dysfunction in corneal disease, emerging treatments may prevent or reduce visual loss.
    Keywords:  Antioxidants; Cornea; Fuchs endothelial dystrophy; Kearns Sayre Syndrome; Keratoconus; Mitochondria; Oxidative stress
  5. Alzheimers Dement. 2017 May 10. pii: S1552-5260(17)30148-6. [Epub ahead of print]
      INTRODUCTION: Family history (FH) of Alzheimer's disease (AD) affects mitochondrial function and may modulate effects of translocase of the outer mitochondrial membrane 40 kDa (TOMM40) rs10524523 ('523) poly-T length on memory decline.METHODS: For 912 nonapolipoprotein ε4 middle-aged adults and 365 aged adults across the AD spectrum, linear mixed models gauged FH and TOMM40 '523 interactions on memory and global cognition between baseline and up to 10 years later. A cerebrospinal fluid mitochondrial function biomarker was also assessed.
    RESULTS: For FH negative participants, gene-dose preservation of memory and global cognition was seen for "very long" versus "short" carriers. For FH positive, an opposite gene-dose decline was seen for very long versus short carriers. Maternal FH was a stronger predictor in aged, but not middle-aged, participants. Similar gene-dose effects were seen for the mitochondrial biomarker aspartate aminotransferase.
    DISCUSSION: These results may clarify conflicting findings on TOMM40 poly-T length and AD-related decline.
    Keywords:  Alzheimer's disease; Aspartate aminotransferase; Global function; Memory; Mitochondrial function; TOMM40
  6. J Exp Bot. 2017 May 26.
      Plants have an RNA editing mechanism that prevents deleterious organelle mutations from resulting in impaired proteins. A typical flowering plant modifies about 40 cytidines in chloroplast transcripts and many hundreds of cytidines in mitochondrial transcripts. The plant editosome, the molecular machinery responsible for this process, contains members of several protein families, including the organelle RNA recognition motif (ORRM)-containing family. ORRM1 and ORRM6 are chloroplast editing factors, while ORRM2, ORRM3, and ORRM4 are mitochondrial editing factors. Here we report the identification of organelle RRM protein 5 (ORRM5) as a mitochondrial editing factor with a unique mode of action. Unlike other ORRM editing factors, the absence of ORRM5 in orrm5 mutant plants results in an increase of the editing extent in 14% of the mitochondrial sites surveyed. The orrm5 mutant also exhibits a reduced splicing efficiency of the first nad5 intron and slower growth and delayed flowering time. ORRM5 contains an RNA recognition motif (RRM) and a glycine-rich domain at the C terminus. The RRM provides the editing activity of ORRM5 and is able to complement the splicing but not the morphological defects.
    Keywords:  Glycine-rich; RNA editing.; mitochondria; plant development; plant editosome; plant stress response
  7. BMC Genomics. 2017 May 26. 18(1): 414
      BACKGROUND: To date, mitochondrial genomes of more than one hundred flatworms (Platyhelminthes) have been sequenced. They show a high degree of similarity and a strong taxonomic bias towards parasitic lineages. The mitochondrial gene atp8 has not been confidently annotated in any flatworm sequenced to date. However, sampling of free-living flatworm lineages is incomplete. We addressed this by sequencing the mitochondrial genomes of the two small-bodied (about 1 mm in length) free-living flatworms Stenostomum sthenum and Macrostomum lignano as the first representatives of the earliest branching flatworm taxa Catenulida and Macrostomorpha respectively.RESULTS: We have used high-throughput DNA and RNA sequence data and PCR to establish the mitochondrial genome sequences and gene orders of S. sthenum and M. lignano. The mitochondrial genome of S. sthenum is 16,944 bp long and includes a 1,884 bp long inverted repeat region containing the complete sequences of nad3, rrnS, and nine tRNA genes. The model flatworm M. lignano has the smallest known mitochondrial genome among free-living flatworms, with a length of 14,193 bp. The mitochondrial genome of M. lignano lacks duplicated genes, however, tandem repeats were detected in a non-coding region. Mitochondrial gene order is poorly conserved in flatworms, only a single pair of adjacent ribosomal or protein-coding genes - nad4l-nad4 - was found in S. sthenum and M. lignano that also occurs in other published flatworm mitochondrial genomes. Unexpectedly, we unambiguously identified the full metazoan mitochondrial protein-coding gene complement including atp8 in S. sthenum and M. lignano. A subsequent search detected atp8 in all mitochondrial genomes of polyclad flatworms published to date, although the gene wasn't previously annotated in these species.
    CONCLUSIONS: Manual, but not automated genome annotation revealed the presence of atp8 in basally branching free-living flatworms, signifying both the importance of manual data curation and of diverse taxon sampling. We conclude that the loss of atp8 within flatworms is restricted to the parasitic taxon Neodermata.
    Keywords:  Duplications; Evolution; Flatworms; Gene order; Mitochondrial genomes; Tandem repeats; atp8