bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2018–02–11
two papers selected by
Gavin McStay, New York Institute of Technology
  1. Myosin VI-Dependent Actin Cages Encapsulate Parkin-Positive Damaged Mitochondria.
  2. Disclosing the functional changes of two genetic alterations in a patient with Chronic Progressive External Ophthalmoplegia: Report of the novel mtDNA m.7486G>A variant.
  1. Dev Cell. 2018 Jan 31. pii: S1534-5807(18)30007-8. [Epub ahead of print]
    Myosin VI-Dependent Actin Cages Encapsulate Parkin-Positive Damaged Mitochondria.
    Antonina J Kruppa, Chieko Kishi-Itakura, Thomas A Masters, Joanna E Rorbach, Guinevere L Grice, John Kendrick-Jones, James A Nathan, Michal Minczuk, Folma Buss.
      Mitochondrial quality control is essential to maintain cellular homeostasis and is achieved by removing damaged, ubiquitinated mitochondria via Parkin-mediated mitophagy. Here, we demonstrate that MYO6 (myosin VI), a unique myosin that moves toward the minus end of actin filaments, forms a complex with Parkin and is selectively recruited to damaged mitochondria via its ubiquitin-binding domain. This myosin motor initiates the assembly of F-actin cages to encapsulate damaged mitochondria by forming a physical barrier that prevents refusion with neighboring populations. Loss of MYO6 results in an accumulation of mitophagosomes and an increase in mitochondrial mass. In addition, we observe downstream mitochondrial dysfunction manifesting as reduced respiratory capacity and decreased ability to rely on oxidative phosphorylation for energy production. Our work uncovers a crucial step in mitochondrial quality control: the formation of MYO6-dependent actin cages that ensure isolation of damaged mitochondria from the network.
    Keywords:  MYO6; NDP52; OPTN; Parkin; TAX1BP1; actin; mitochondrial quality control; mitophagy; myosin VI
    DOI:  https://doi.org/10.1016/j.devcel.2018.01.007
  2. Neuromuscul Disord. 2017 Nov 23. pii: S0960-8966(17)30452-2. [Epub ahead of print]
    Disclosing the functional changes of two genetic alterations in a patient with Chronic Progressive External Ophthalmoplegia: Report of the novel mtDNA m.7486G>A variant.
    Mafalda Bacalhau, Marta Simões, Mariana C Rocha, Steven A Hardy, Amy E Vincent, João Durães, Maria C Macário, Maria João Santos, Olinda Rebelo, Carla Lopes, João Pratas, Cândida Mendes, Mónica Zuzarte, A Cristina Rego, Henrique Girão, Lee-Jun C Wong, Robert W Taylor, Manuela Grazina.
      Chronic Progressive External Ophthalmoplegia (CPEO) is characterized by ptosis and ophthalmoplegia and is usually caused by mitochondrial DNA (mtDNA) deletions or mt-tRNA mutations. The aim of the present work was to clarify the genetic defect in a patient presenting with CPEO and elucidate the underlying pathogenic mechanism. This 62-year-old female first developed ptosis of the right eye at the age of 12 and subsequently the left eye at 45 years, and was found to have external ophthalmoplegia at the age of 55 years. Histopathological abnormalities were detected in the patient's muscle, including ragged-red fibres, a mosaic pattern of COX-deficient muscle fibres and combined deficiency of respiratory chain complexes I and IV. Genetic investigation revealed the "common deletion" in the patient's muscle and fibroblasts. Moreover, a novel, heteroplasmic mt-tRNASer(UCN) variant (m.7486G>A) in the anticodon loop was detected in muscle homogenate (50%), fibroblasts (11%) and blood (4%). Single-fibre analysis showed segregation with COX-deficient fibres for both genetic alterations. Assembly defects of mtDNA-encoded complexes were demonstrated in fibroblasts. Functional analyses showed significant bioenergetic dysfunction, reduction in respiration rate and ATP production and mitochondrial depolarization. Multilamellar bodies were detected by electron microscopy, suggesting disturbance in autophagy. In conclusion, we report a CPEO patient with two possible genetic origins, both segregating with biochemical and histochemical defect. The "common mtDNA deletion" is the most likely cause, yet the potential pathogenic effect of a novel mt-tRNASer(UCN) variant cannot be fully excluded.
    Keywords:  Bioenergetic dysfunction; CPEO; Translation defect; mt-tRNA variant (m.7486G>A); mtDNA common deletion
    DOI:  https://doi.org/10.1016/j.nmd.2017.11.006
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