bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2020‒02‒16
eleven papers selected by
Gavin McStay
Staffordshire University


  1. Genes (Basel). 2020 Feb 12. pii: E192. [Epub ahead of print]11(2):
    Mustafa MF, Fakurazi S, Abdullah MA, Maniam S.
      Mitochondria are best known for their role in energy production, and they are the only mammalian organelles that contain their own genomes. The mitochondrial genome mutation rate is reported to be 10-17 times higher compared to nuclear genomes as a result of oxidative damage caused by reactive oxygen species during oxidative phosphorylation. Pathogenic mitochondrial DNA mutations result in mitochondrial DNA disorders, which are among the most common inherited human diseases. Interventions of mitochondrial DNA disorders involve either the transfer of viable isolated mitochondria to recipient cells or genetically modifying the mitochondrial genome to improve therapeutic outcome. This review outlines the common mitochondrial DNA disorders and the key advances in the past decade necessary to improve the current knowledge on mitochondrial disease intervention. Although it is now 31 years since the first description of patients with pathogenic mitochondrial DNA was reported, the treatment for mitochondrial disease is often inadequate and mostly palliative. Advancements in diagnostic technology improved the molecular diagnosis of previously unresolved cases, and they provide new insight into the pathogenesis and genetic changes in mitochondrial DNA diseases.
    Keywords:  genetic intervention; mitochondria DNA mutations; mitochondria transfer; mitochondrial DNA; mitochondrial DNA diseases
    DOI:  https://doi.org/10.3390/genes11020192
  2. Neurol Genet. 2020 Feb;6(1): e381
    Bugiardini E, Bottani E, Marchet S, Poole OV, Beninca C, Horga A, Woodward C, Lam A, Hargreaves I, Chalasani A, Valerio A, Lamantea E, Venner K, Holton JL, Zeviani M, Houlden H, Quinlivan R, Lamperti C, Hanna MG, Pitceathly RDS.
      Objective: To describe the clinical and functional consequences of 1 novel and 1 previously reported truncating MT-ATP6 mutation.Methods: Three unrelated probands with mitochondrial encephalomyopathy harboring truncating MT-ATP6 mutations are reported. Transmitochondrial cybrid cell studies were used to confirm pathogenicity of 1 novel variant, and the effects of all 3 mutations on ATPase 6 and complex V structure and function were investigated.
    Results: Patient 1 presented with adult-onset cerebellar ataxia, chronic kidney disease, and diabetes, whereas patient 2 had myoclonic epilepsy and cerebellar ataxia; both harbored the novel m.8782G>A; p.(Gly86*) mutation. Patient 3 exhibited cognitive decline, with posterior white matter abnormalities on brain MRI, and severely impaired renal function requiring transplantation. The m.8618dup; p.(Thr33Hisfs*32) mutation, previously associated with neurogenic muscle weakness, ataxia, and retinitis pigmentosa, was identified. All 3 probands demonstrated a broad range of heteroplasmy across different tissue types. Blue-native gel electrophoresis of cultured fibroblasts and skeletal muscle tissue confirmed multiple bands, suggestive of impaired complex V assembly. Microscale oxygraphy showed reduced basal respiration and adenosine triphosphate synthesis, while reactive oxygen species generation was increased. Transmitochondrial cybrid cell lines studies confirmed the deleterious effects of the novel m.8782 G>A; p.(Gly86*) mutation.
    Conclusions: We expand the clinical and molecular spectrum of MT-ATP6-related mitochondrial disorders to include leukodystrophy, renal disease, and myoclonic epilepsy with cerebellar ataxia. Truncating MT-ATP6 mutations may exhibit highly variable mutant levels across different tissue types, an important consideration during genetic counseling.
    DOI:  https://doi.org/10.1212/NXG.0000000000000381
  3. Neurol Genet. 2020 Feb;6(1): e391
    Hedberg-Oldfors C, Macao B, Basu S, Lindberg C, Peter B, Erdinc D, Uhler JP, Larsson E, Falkenberg M, Oldfors A.
      Objective: To determine the pathogenicity of a novel POLG mutation in a man with late-onset autosomal recessive progressive external ophthalmoplegia using clinical, molecular, and biochemical analyses.Methods: A multipronged approach with detailed neurologic examinations, muscle biopsy analyses, molecular genetic studies, and in vitro biochemical characterization.
    Results: The patient had slowly progressive bilateral ptosis and severely reduced horizontal and vertical gaze. Muscle biopsy showed slight variability in muscle fiber size, scattered ragged red fibers, and partial cytochrome c oxidase deficiency. Biallelic mutations were identified in the POLG gene encoding the catalytic A subunit of POLγ. One allele carried a novel mutation in the exonuclease domain (c.590T>C; p.F197S), and the other had a previously characterized null mutation in the polymerase domain (c.2740A>C; p.T914P). Biochemical characterization revealed that the novel F197S mutant protein had reduced exonuclease and DNA polymerase activities and confirmed that T914P was inactive. By deep sequencing of mitochondrial DNA (mtDNA) extracted from muscle, multiple large-scale rearrangements were mapped and quantified.
    Conclusions: The patient's phenotype was caused by biallelic POLG mutations, resulting in one inactive POLγA protein (T914P) and one with decreased polymerase and exonuclease activity (F197S). The reduction in polymerase activity explains the presence of multiple pathogenic large-scale deletions in the patient's mtDNA.
    DOI:  https://doi.org/10.1212/NXG.0000000000000391
  4. Ann Transl Med. 2020 Jan;8(1): 17
    Zhang L, Zhang Z, Khan A, Zheng H, Yuan C, Jiang H.
      Mitochondrial diseases are a group of clinically and genetically heterogeneous disorders driven by oxidative phosphorylation dysfunction of the mitochondrial respiratory chain which due to pathogenic mutations of mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Recent progress in molecular genetics and biochemical methodologies has provided a better understanding of the etiology and pathogenesis of mitochondrial diseases, and this has expanded the clinical spectrum of this conditions. But the treatment of mitochondrial diseases is largely symptomatic and thus does not significantly change the course of the disease. Few clinical trials have led to the design of drugs aiming at enhancing mitochondrial function or reversing the consequences of mitochondrial dysfunction which are now used in the clinical treatment of mitochondrial diseases. Several other drugs are currently being evaluated for clinical management of patients with mitochondrial diseases. In this review, the current status of treatments for mitochondrial diseases is described systematically, and newer potential treatment strategies for mitochondrial diseases are also discussed.
    Keywords:  Mitochondrial diseases; drug therapy; electron transfer chain; mitochondrial biogenesis; mitochondrial dynamics
    DOI:  https://doi.org/10.21037/atm.2019.10.113
  5. Neurol Genet. 2020 Feb;6(1): e393
    Stendel C, Neuhofer C, Floride E, Yuqing S, Ganetzky RD, Park J, Freisinger P, Kornblum C, Kleinle S, Schöls L, Distelmaier F, Stettner GM, Büchner B, Falk MJ, Mayr JA, Synofzik M, Abicht A, Haack TB, Prokisch H, Wortmann SB, Murayama K, Fang F, Klopstock T, .
      Objective: To delineate the phenotypic and genotypic spectrum in carriers of mitochondrial MT-ATP6 mutations in a large international cohort.Methods: We analyzed in detail the clinical, genetical, and neuroimaging data from 132 mutation carriers from national registries and local databases from Europe, USA, Japan, and China.
    Results: We identified 113 clinically affected and 19 asymptomatic individuals with a known pathogenic MT-ATP6 mutation. The most frequent mutations were m.8993 T > G (53/132, 40%), m.8993 T > C (30/132, 23%), m.9176 T > C (30/132, 23%), and m.9185 T > C (12/132, 9%). The degree of heteroplasmy was high both in affected (mean 95%, range 20%-100%) and unaffected individuals (mean 73%, range 20%-100%). Age at onset ranged from prenatal to the age of 75 years, but almost half of the patients (49/103, 48%) became symptomatic before their first birthday. In 28 deceased patients, the median age of death was 14 months. The most frequent symptoms were ataxia (81%), cognitive dysfunction (49%), neuropathy (48%), seizures (37%), and retinopathy (14%). A diagnosis of Leigh syndrome was made in 55% of patients, whereas the classic syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP) was rare (8%).
    Conclusions: In this currently largest series of patients with mitochondrial MT-ATP6 mutations, the phenotypic spectrum ranged from asymptomatic to early onset multisystemic neurodegeneration. The degree of mutation heteroplasmy did not reliably predict disease severity. Leigh syndrome was found in more than half of the patients, whereas classic NARP syndrome was rare. Oligosymptomatic presentations were rather frequent in adult-onset patients, indicating the need to include MT-ATP6 mutations in the differential diagnosis of both ataxias and neuropathies.
    DOI:  https://doi.org/10.1212/NXG.0000000000000393
  6. Mitochondrion. 2020 Feb 08. pii: S1567-7249(19)30106-0. [Epub ahead of print]
    Endou M, Yoshida K, Hirota M, Nakajima C, Sakaguchi A, Komatsubara N, Kurihara Y.
      We identified Coxfa4l3, previously called C15orf48 or Nmes1, as a novel accessory protein of Complex IV of the mitochondrial electron transport chain (ETC). Amino acid sequence comparison, the intracellular localization and the protein expression data showed that the protein is the third isoform of Coxfa4 and the expression of Coxfa4 and Coxfa4l3 proteins during spermatogenesis showed a mutually exclusive pattern, implying that Coxfa4 replaces Coxfa4l3 in Complex IV after meiosis. These results may provide some insight into the unique mechanism of ATP production in late spermatogenesis.
    Keywords:  electron transport chain; hypoxia; spermatogenesis
    DOI:  https://doi.org/10.1016/j.mito.2020.02.003
  7. Mol Biol Cell. 2020 Feb 12. mbcE19060329
    Basch M, Wagner M, Rolland S, Carbonell A, Zeng R, Khosravi S, Schmidt A, Aftab W, Imhof A, Wagener J, Conradt B, Wagener N.
      The mitochondrial AAA ATPase Msp1 is well known for extraction of mis-localized tail-anchored ER proteins from the mitochondrial outer membrane. Here, we analyzed the extraction of precursors blocking the import pore in the outer membrane. We demonstrate strong genetic interactions of Msp1 and the proteasome with components of the TOM complex, the main translocase in the outer membrane. Msp1 and the proteasome both contribute to the removal of arrested precursor proteins that specifically accumulate in these mutants. The proteasome activity is essential for the removal as proteasome inhibitors block extraction. Furthermore, the proteasomal subunit Rpn10 co-purified with Msp1. The human Msp1 homologue has been implicated in neurodegenerative diseases and we show that the lack of the Caenorhabditis elegans Msp1 homologue triggers an import stress response in the worm, which indicates a conserved role in metazoa. In summary, our results suggest a role of Msp1 as adaptor for the proteasome which drives the extraction of arrested and mis-localized proteins at the mitochondrial outer membrane.
    DOI:  https://doi.org/10.1091/mbc.E19-06-0329
  8. Infect Immun. 2020 Feb 10. pii: IAI.00738-19. [Epub ahead of print]
    Yuan J, Zheng Z, Wang L, Ran H, Tang X, Xie X, Li F, Liu F, Wang X, Zhang J, Zhang J, Huang Y, Xia X, Wan Y.
      Cellular membrane proteins are a critical part of the host defense mechanisms against infection and intracellular survival of Listeria monocytogenes The complex spatiotemporal regulation of bacterial infection by various membrane proteins has been challenging to study. Here, using mass spectrometry analyses, we depicted the dynamic expression landscape of membrane proteins upon L. monocytogenes infection in dendritic cells. We showed that Dynein light chain 1 (Dynll1) formed a persistent complex with the mitochondrial cytochrome oxidase, Cox4i1 that is disturbed by pathogen insult. We discovered that the dissociation of the Dynll1-Cox4i1 complex is required for the release of mitochondrial reactive oxygen species and serves as a regulator of intracellular proliferation of Listeria monocytogenes Our study shows that Dynll1 is an inhibitor of mitochondrial reactive oxygen species and can serve as a potential molecular drug target for antibacterial treatment.
    DOI:  https://doi.org/10.1128/IAI.00738-19
  9. Curr Opin Struct Biol. 2020 Feb 10. pii: S0959-440X(20)30004-X. [Epub ahead of print]63 1-9
    Parey K, Wirth C, Vonck J, Zickermann V.
      Respiratory complex I is an intricate multi-subunit membrane protein with a central function in aerobic energy metabolism. During the last years, structures of mitochondrial complex I and respiratory supercomplexes were determined by cryo-EM at increasing resolution. Structural and computational studies have shed light on the dynamics of proton translocation pathways, the interaction of complex I with lipids and the unusual access pathway of ubiquinone to the active site. Recent advances in understanding complex I function include characterization of specific conformational changes that are critical for proton pumping. Cryo-EM structures of the NADH dehydrogenase-like (NDH) complex of photosynthesis and a bacterial membrane bound hydrogenase (MBH) have provided a broader perspective on the complex I superfamily.
    DOI:  https://doi.org/10.1016/j.sbi.2020.01.004
  10. Nat Struct Mol Biol. 2020 Feb;27(2): 202-209
    Tang WK, Borgnia MJ, Hsu AL, Esser L, Fox T, de Val N, Xia D.
      The mitochondrial membrane-bound AAA protein Bcs1 translocate substrates across the mitochondrial inner membrane without previous unfolding. One substrate of Bcs1 is the iron-sulfur protein (ISP), a subunit of the respiratory Complex III. How Bcs1 translocates ISP across the membrane is unknown. Here we report structures of mouse Bcs1 in two different conformations, representing three nucleotide states. The apo and ADP-bound structures reveal a homo-heptamer and show a large putative substrate-binding cavity accessible to the matrix space. ATP binding drives a contraction of the cavity by concerted motion of the ATPase domains, which could push substrate across the membrane. Our findings shed light on the potential mechanism of translocating folded proteins across a membrane, offer insights into the assembly process of Complex III and allow mapping of human disease-associated mutations onto the Bcs1 structure.
    DOI:  https://doi.org/10.1038/s41594-020-0373-0
  11. Sci Rep. 2020 Feb 13. 10(1): 2599
    Polovina ES, Parakatselaki ME, Ladoukakis ED.
      Mitochondrial DNA (mtDNA) is maternally transmitted in animals and therefore, individuals are expected to have a single mtDNA haplotype (homoplasmy). Yet, heteroplasmic individuals have been observed in a large number of animal species. Heteroplasmy may emerge as a result of somatic mtDNA mutations, paternal leakage during fertilization or be inherited from a heteroplasmic mother. Understanding the causes of heteroplasmy could shed light into the evolution of mtDNA inheritance. In this study we examined heteroplasmy in progeny from heterospecific crosses of Drosophila for two consecutive generations. We studied the generation of heteroplasmy from paternal leakage and the maternal transmission of heteroplasmy. Our data reveal non-random patterns in the emergence and transmission of heteroplasmy and suggest that heteroplasmy depends on the family of origin.
    DOI:  https://doi.org/10.1038/s41598-020-59194-x