bims-cytox1 Biomed news
on Cytochrome oxidase subunit 1
Issue of 2018‒11‒11
four papers selected by
Gavin McStay
Staffordshire University


  1. Biochim Biophys Acta Mol Basis Dis. 2018 Oct 31. pii: S0925-4439(18)30437-X. [Epub ahead of print]1865(1): 98-106
    Terburgh K, Lindeque Z, Mason S, van der Westhuizen F, Louw R.
      Leigh syndrome is one of the most common childhood-onset neurometabolic disorders resulting from a primary oxidative phosphorylation dysfunction and affecting mostly brain tissues. Ndufs4-/- mice have been widely used to study the neurological responses in this syndrome, however the reason why these animals do not display strong muscle involvement remains elusive. We combined biochemical strategies and multi-platform metabolomics to gain insight into the metabolism of both glycolytic (white quadriceps) and oxidative (soleus) skeletal muscles from Ndufs4-/- mice. Enzyme assays confirmed severely reduced (80%) CI activity in both Ndufs4-/- muscle types, compared to WTs. No significant alterations were evident in other respiratory chain enzyme activities; however, Ndufs4-/- solei displayed moderate decreases in citrate synthase (12%) and CIII (18%) activities. Through hypothesis-generating metabolic profiling, we provide the first evidence of adaptive responses to CI dysfunction involving non-classical pathways fueling the ubiquinone (Q) cycle. We report a respective 48 and 34 discriminatory metabolites between Ndufs4-/- and WT white quadriceps and soleus muscles, among which the most prominent alterations indicate the involvement of the glycerol-3-phosphate shuttle, electron transfer flavoprotein system, CII, and proline cycle in fueling the Q cycle. By restoring the electron flux to CIII via the Q cycle, these adaptive mechanisms could maintain adequate oxidative ATP production, despite CI deficiency. Taken together, our results shed light on the underlying pathogenic mechanisms of CI dysfunction in skeletal muscle. Upon further investigation, these pathways could provide novel targets for therapeutic intervention in CI deficiency and potentially lead to the development of new treatment strategies.
    Keywords:  Complex I deficiency; Metabolomics; Mitochondrial disease; Ndufs4 knockout mice; Skeletal muscle; Ubiquinone-cycle
    DOI:  https://doi.org/10.1016/j.bbadis.2018.10.034
  2. Pediatr Neurol. 2018 Aug 09. pii: S0887-8994(18)30070-5. [Epub ahead of print]
    Remtulla S, Emilie Nguyen CT, Prasad C, Campbell C.
      BACKGROUND: Autosomal recessive mutations in the nuclear Twinkle (C10orf2) gene cause a mitochondrial DNA depletion syndrome (MDS) characterized by early onset hepatoencephalopathy.METHODS: We report a severe, early onset encephalopathy and multisystem failure case caused by novel recessive Twinkle gene mutations. Patient clinical, laboratory, and pathological features are reported and Twinkle-associated MDS literature reviewed.
    RESULTS: Typical presentation includes symptom onset before age six months, failure to thrive, psychomotor regression, epileptic encephalopathy, sensory axonal neuropathy, cholestatic liver dysfunction, and occasionally, renal tubulopathy, movement disorders, and ophthalmoplegia. Death is typical before age four years.
    CONCLUSIONS: In the differential diagnosis of early onset encephalopathy and multisystem failure, MDS should be considered.
    Keywords:  C10orf2; PEO1; TWINKLE; encephalopathy; hepatocerebral syndrome; liver; mitochondrial DNA depletion syndrome; mtDNA
    DOI:  https://doi.org/10.1016/j.pediatrneurol.2018.08.007
  3. Reprod Biol Endocrinol. 2018 Nov 03. 16(1): 110
    Li L, Wu CS, Hou GM, Dong MZ, Wang ZB, Hou Y, Schatten H, Zhang GR, Sun QY.
      BACKGROUND: Diabetes induces many complications including reduced fertility and low oocyte quality, but whether it causes increased mtDNA mutations is unknown.METHODS: We generated a T2D mouse model by using high-fat-diet (HFD) and Streptozotocin (STZ) injection. We examined mtDNA mutations in oocytes of diabetic mice by high-throughput sequencing techniques.
    RESULTS: T2D mice showed glucose intolerance, insulin resistance, low fecundity compared to the control group. T2D oocytes showed increased mtDNA mutation sites and mutation numbers compared to the control counterparts. mtDNA mutation examination in F1 mice showed that the mitochondrial bottleneck could eliminate mtDNA mutations.
    CONCLUSIONS: T2D mice have increased mtDNA mutation sites and mtDNA mutation numbers in oocytes compared to the counterparts, while these adverse effects can be eliminated by the bottleneck effect in their offspring. This is the first study using a small number of oocytes to examine mtDNA mutations in diabetic mothers and offspring.
    Keywords:  Bottleneck; Diabetes; Oocyte; mtDNA mutation
    DOI:  https://doi.org/10.1186/s12958-018-0423-1
  4. Metab Brain Dis. 2018 Nov 03.
    Salama M, El-Desouky S, Alsayed A, El-Hussiny M, Moustafa A, Taalab Y, Mohamed W.
      Leigh syndrome (LS) is one of the most puzzling mitochondrial disorders, which is also known as subacute necrotizing encephalopathy. It has an incidence of 1 in 77,000 live births worldwide with poor prognosis. Currently, there is a poor understanding of the underlying pathophysiological mechanisms of the disease without any available effective treatment. Hence, the inevitability for developing suitable animal and cellular models needed for the development of successful new therapeutic modalities. In this short report, we blocked FOXRED1 gene with small interfering RNA (siRNA) using C57bl/6 mice. Results showed neurobehavioral changes in the injected mice along with parallel degeneration in corpus striatum and sparing of the substantia nigra similar to what happen in Leigh syndrome cases. FOXRED1 blockage could serve as a new animal model for Leigh syndrome due to defective CI, which echoes damage to corpus striatum and affection of the central dopaminergic system in this disease. Further preclinical studies are required to validate this model.
    Keywords:  FOXRED1; Gene silencing; Leigh syndrome; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s11011-018-0334-z