bims-cytox1 Biomed news
on Cytochrome oxidase subunit 1
Issue of 2018‒04‒08
four papers selected by
Gavin McStay
New York Institute of Technology

  1. Trends Mol Med. 2018 Mar 28. pii: S1471-4914(18)30048-0. [Epub ahead of print]
    Adashi EY, Cohen IG.
      Mutant mitochondrial DNA gives rise to a broad range of incurable inborn maladies. Prevention may now be possible by replacing the mutation-carrying mitochondria of zygotes or oocytes at risk with donated unaffected counterparts. However, mitochondrial replacement therapy is being held back by theological, ethical, and safety concerns over the loss of human zygotes and the involvement of a donor. These concerns make it plain that the identification, validation, and regulatory adjudication of novel embryo-sparing donor-independent technologies remains a pressing imperative. This Opinion highlights three emerging embryo-sparing donor-independent options that stand to markedly allay theological, ethical, and safety concerns raised by mitochondrial replacement therapy.
    Keywords:  in vitro oogenesis; maternal spindle transfer; mitochondrial gene therapy; mitochondrial genome editing; mitochondrial replacement therapy; polar body transfer; pronuclear transfer
  2. Int J Pediatr Otorhinolaryngol. 2018 May;pii: S0165-5876(18)30110-1. [Epub ahead of print]108 125-131
    Matsushima K, Nakano A, Arimoto Y, Mutai H, Yamazawa K, Murayama K, Matsunaga T.
      OBJECTIVE: Hearing loss caused by mutation of mitochondrial DNA typically develops in late childhood or early adulthood, but rarely in infancy. We report the investigation of a patient to determine the cause of his early onset hearing loss.MATERIALS AND METHODS: The proband was a boy aged 1 year and 2 months at presentation. Newborn hearing screening test by automated auditory brainstem response generated "pass" results for both ears. His reaction to sound deteriorated by 9 months. Average pure tone threshold at 0.5, 1, and 2 kHz was 55 dB by conditioned orientation response audiometry. His father had congenital hearing loss, and his mother had progressive hearing loss since childhood. Invader assays and Sanger sequencing were performed to investigate genetic causes of the hearing loss in the proband, and heteroplasmy was assessed by PCR-restriction fragment length polymorphism, Sanger sequencing, and pyrosequencing. Additionally, mitochondrial function was evaluated by measurement of the oxygen consumption rate of patient skin fibroblasts.
    RESULTS: An m.7445A > G mitochondrial DNA mutation and a heterozygous c.235delC (p.L79Cfs*3) mutation of GJB2 were detected in the proband. His mother carried the m.7445A > G mitochondrial DNA mutation, and his father was a compound heterozygote for GJB2 mutations (c.[235delC]; [134G > A; 408C > A]). Tissue samples from both the proband and his mother exhibited a high degree of heteroplasmy. Fibroblasts from the proband exhibited markedly reduced oxygen consumption rates. These data indicate that the proband had impaired mitochondrial function, resulting in hearing loss.
    CONCLUSION: This research demonstrates that hearing loss in a proband who presented in infancy and that of his mother resulted from a high level of heteroplasmy for the m.7445A > G mitochondrial DNA mutation, indicating that this alteration can cause hearing loss in infancy.
    Keywords:  Heteroplasmy; Infant; Mitochondrial DNA; Progressive hearing loss
  3. J Mol Cell Cardiol. 2018 Mar 29. pii: S0022-2828(18)30091-9. [Epub ahead of print]
    Zhang G, Sheng M, Wang J, Teng T, Sun Y, Yang Q, Xu Z.
      Serine 727 (Ser727) phosphorylation of STAT3 plays a role in the regulation of mitochondrial respiration. This study aimed to test if zinc could regulate mitochondrial respiration through phosphorylation of STAT3 at Ser727 in the setting of ischemia/reperfusion in the heart. Under normoxic conditions, treatment of isolated rat hearts with ZnCl2 increased cytosolic STAT3 phosphorylation at Ser727 followed by phospho-STAT3 translocation to mitochondria. In isolated rat hearts subjected to 30 min regional ischemia followed by 20 min of reperfusion, ZnCl2 given 5 min before the onset of reperfusion also increased mitochondrial phospho-STAT3. ZnCl2 enhanced ERK phosphorylation and PD98059 reversed the effect of ZnCl2 on STAT3 phosphorylation. ZnCl2 improved the mitochondrial oxidative phosphorylation at reperfusion. This effect was abolished by STAT3S727A, a mutant in which Ser727 is replaced with alanine, in H9c2 cells subjected to hypoxia/reoxygenation. In addition, ZnCl2 increased the mRNA level of the complex I subunit ND6, which was also reversed by STAT3S727A. Moreover, ZnCl2 attenuated mitochondrial ROS generation and dissipation of mitochondrial membrane potential (ΔΨm) at reoxygenation through Ser727 phosphorylation. Finally, ZnCl2 suppression of succinate dehydrogenase (SDH) activity upon the onset of reperfusion was nullified by the Ser727 mutation. In conclusion, zinc improves cardiac oxidative phosphorylation and inhibits mitochondrial ROS generation at reperfusion by increasing mitochondrial STAT3 phosphorylation at Ser727 via ERK. The preservation of ND6 mtDNA and the inhibition of SDH activity may account for the role of STAT3 in the beneficial action of zinc on the mitochondrial oxidative phosphorylation and ROS generation at reperfusion.
    Keywords:  Mitochondria; SDH; STAT3; Zinc; mtDNA
  4. Ann Neurol. 2018 Mar 31.
    Jonikas M, Madill M, Mathy A, Zekoll T, Zois CE, Wigfield S, Kurzawa-Akanbi M, Browne C, Sims D, Chinnery PF, Cowley SA, Tofaris GK.
      OBJECTIVE: Defective mitochondrial function due to OPA1 mutations causes primarily optic atrophy and less commonly neurodegenerative syndromes. The pathomechanism by which OPA1 mutations trigger diffuse loss of neurons in some but not all patients is unknown. Here we used a tractable iPSC-based model to capture the biology of OPA1 haploinsufficiency in cases presenting with classic eye disease versus syndromic parkinsonism.METHODS: iPSC were generated from two patients with OPA1 haploinsufficiency and two controls and differentiated into dopaminergic neurons. Metabolic profile was determined by extracellular flux analysis, respiratory complex levels using immunoblotting and complex I activity by a colorimetric assay. Mitochondria were examined by transmission electron microscopy. Mitochondrial DNA copy number and deletions were assayed using long range PCR. Mitochondrial membrane potential was measured by TMRM uptake and mitochondrial fragmentation was assessed by confocal microscopy. Exome sequencing was used to screen for pathogenic variants.
    RESULTS: OPA1 haploinsufficient iPSC differentiated into dopaminergic neurons and exhibited marked reduction in OPA1 protein levels. Loss of OPA1 caused a late defect in oxidative phosphorylation, reduced complex I levels and activity without a significant change in the ultrastructure of mitochondria. Loss of neurons in culture recapitulated dopaminergic degeneration in syndromic disease and correlated with mitochondrial fragmentation.
    INTERPRETATION: OPA1 levels maintain oxidative phosphorylation in iPSC-derived neurons at least in part by regulating the stability of Complex I. Severity of OPA1 disease associates primarily with the extent of OPA1-mediated fusion, suggesting that activation of this mechanism or identification of its genetic modifiers may have therapeutic or prognostic value. This article is protected by copyright. All rights reserved.
    Keywords:  Mitochondria; Parkinsonism; iPSC-models