bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2021‒01‒31
eight papers selected by
Gavin McStay
Staffordshire University


  1. FEBS Lett. 2021 Jan 29.
    Richter U, McFarland R, Taylor RW, Pickett SJ.
      Mitochondrial diseases are clinically and genetically heterogeneous disorders, caused by pathogenic variants in either the nuclear or mitochondrial genome. This heterogeneity is particularly striking for disease caused by variants in mitochondrial DNA-encoded tRNA (mt-tRNA) genes, posing challenges for both the treatment of patients and for understanding the molecular pathology. In this review, we consider disease caused by the two most common pathogenic mt-tRNA variants: m.3243A>G (within MT-TL1, encoding mt-tRNALeu(UUR) ) and m.8344A>G (within MT-TK, encoding mt-tRNALys ), which together account for the vast majority of all mt-tRNA-related disease. We compare and contrast the clinical disease they are associated with, as well as their molecular pathologies and consider what is known about the likely molecular mechanisms of disease. Finally, we discuss the role of mitochondrial-nuclear cross-talk in the manifestation of mt-tRNA-associated disease and how research in this area has not only the potential to uncover molecular mechanisms responsible for the vast clinical heterogeneity associated with these variants but also pave the way to develop treatment options for these devastating diseases.
    Keywords:  MELAS; MERRF; Mitochondrial disease; heteroplasmy; m.3243A>G; m.8344A>G; mitochondrial DNA; mitochondrial tRNA
    DOI:  https://doi.org/10.1002/1873-3468.14049
  2. Trends Mol Med. 2021 Jan 21. pii: S1471-4914(20)30329-4. [Epub ahead of print]
    Dan J, Memczak S, Izpisua Belmonte JC.
      Genome editing holds great promise for treating a range of human genetic diseases. While emerging clustered regularly interspaced short-palindromic repeats (CRISPR) technologies allow editing of the nuclear genome, it is still not possible to precisely manipulate mitochondrial DNA (mtDNA). Here, we summarize past developments and recent advances in nuclear and mitochondrial genome editing.
    Keywords:  gene therapy; genome editing; mitochondria; translational medicine
    DOI:  https://doi.org/10.1016/j.molmed.2020.12.005
  3. Reprod Med Biol. 2021 Jan;20(1): 53-61
    Yamada M, Sato S, Ooka R, Akashi K, Nakamura A, Miyado K, Akutsu H, Tanaka M.
      Background: Pathogenic mitochondrial (mt)DNA mutations, which often cause life-threatening disorders, are maternally inherited via the cytoplasm of oocytes. Mitochondrial replacement therapy (MRT) is expected to prevent second-generation transmission of mtDNA mutations. However, MRT may affect the function of respiratory chain complexes comprised of both nuclear and mitochondrial proteins.Methods: Based on the literature and current regulatory guidelines (especially in Japan), we analyzed and reviewed the recent developments in human models of MRT.
    Main findings: MRT does not compromise pre-implantation development or stem cell isolation. Mitochondrial function in stem cells after MRT is also normal. Although mtDNA carryover is usually less than 0.5%, even low levels of heteroplasmy can affect the stability of the mtDNA genotype, and directional or stochastic mtDNA drift occurs in a subset of stem cell lines (mtDNA genetic drift). MRT could prevent serious genetic disorders from being passed on to the offspring. However, it should be noted that this technique currently poses significant risks for use in embryos designed for implantation.
    Conclusion: The maternal genome is fundamentally compatible with different mitochondrial genotypes, and vertical inheritance is not required for normal mitochondrial function. Unresolved questions regarding mtDNA genetic drift can be addressed by basic research using MRT.
    Keywords:  mitochondrial DNA; mitochondrial DNA carryover; mitochondrial disease; mitochondrial replacement; mtDNA genetic drift
    DOI:  https://doi.org/10.1002/rmb2.12356
  4. Cells. 2021 Jan 20. pii: E197. [Epub ahead of print]10(2):
    Gladyck S, Aras S, Hüttemann M, Grossman LI.
      Oxidative phosphorylation is a tightly regulated process in mammals that takes place in and across the inner mitochondrial membrane and consists of the electron transport chain and ATP synthase. Complex IV, or cytochrome c oxidase (COX), is the terminal enzyme of the electron transport chain, responsible for accepting electrons from cytochrome c, pumping protons to contribute to the gradient utilized by ATP synthase to produce ATP, and reducing oxygen to water. As such, COX is tightly regulated through numerous mechanisms including protein-protein interactions. The twin CX9C family of proteins has recently been shown to be involved in COX regulation by assisting with complex assembly, biogenesis, and activity. The twin CX9C motif allows for the import of these proteins into the intermembrane space of the mitochondria using the redox import machinery of Mia40/CHCHD4. Studies have shown that knockdown of the proteins discussed in this review results in decreased or completely deficient aerobic respiration in experimental models ranging from yeast to human cells, as the proteins are conserved across species. This article highlights and discusses the importance of COX regulation by twin CX9C proteins in the mitochondria via COX assembly and control of its activity through protein-protein interactions, which is further modulated by cell signaling pathways. Interestingly, select members of the CX9C protein family, including MNRR1 and CHCHD10, show a novel feature in that they not only localize to the mitochondria but also to the nucleus, where they mediate oxygen- and stress-induced transcriptional regulation, opening a new view of mitochondrial-nuclear crosstalk and its involvement in human disease.
    Keywords:  ETC complex assembly; Intermembrane space proteins; mitochondrial regulation
    DOI:  https://doi.org/10.3390/cells10020197
  5. Front Genet. 2020 ;11 610764
    Povea-Cabello S, Villanueva-Paz M, Suárez-Rivero JM, Álvarez-Córdoba M, Villalón-García I, Talaverón-Rey M, Suárez-Carrillo A, Munuera-Cabeza M, Sánchez-Alcázar JA.
      Mitochondrial diseases are a heterogeneous group of rare genetic disorders that can be caused by mutations in nuclear (nDNA) or mitochondrial DNA (mtDNA). Mutations in mtDNA are associated with several maternally inherited genetic diseases, with mitochondrial dysfunction as a main pathological feature. These diseases, although frequently multisystemic, mainly affect organs that require large amounts of energy such as the brain and the skeletal muscle. In contrast to the difficulty of obtaining neuronal and muscle cell models, the development of induced pluripotent stem cells (iPSCs) has shed light on the study of mitochondrial diseases. However, it is still a challenge to obtain an appropriate cellular model in order to find new therapeutic options for people suffering from these diseases. In this review, we deepen the knowledge in the current models for the most studied mt-tRNA mutation-caused mitochondrial diseases, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and MERRF (myoclonic epilepsy with ragged red fibers) syndromes, and their therapeutic management. In particular, we will discuss the development of a novel model for mitochondrial disease research that consists of induced neurons (iNs) generated by direct reprogramming of fibroblasts derived from patients suffering from MERRF syndrome. We hypothesize that iNs will be helpful for mitochondrial disease modeling, since they could mimic patient's neuron pathophysiology and give us the opportunity to correct the alterations in one of the most affected cellular types in these disorders.
    Keywords:  direct reprogramming; disease modeling; induced neurons; mitochondrial diseases; mtDNA
    DOI:  https://doi.org/10.3389/fgene.2020.610764
  6. Hum Mutat. 2021 Jan 27.
    Correia SP, Moedas MF, Naess K, Bruhn H, Maffezzini C, Calvo-Garrido J, Lesko N, Wibom R, Schober FA, Jemt A, Stranneheim H, Freyer C, Wedell A, Wredenberg A.
      Mutations in structural subunits and assembly factors of complex I of the oxidative phosphorylation system constitute the most common cause of mitochondrial respiratory chain defects. Such mutations can present a wide range of clinical manifestations, varying from mild deficiencies to severe, lethal disorders. We describe a patient presenting intrauterine growth restriction and anaemia, which displayed postpartum hypertrophic cardiomyopathy, lactic acidosis, encephalopathy, and a severe complex I defect with fatal outcome. Whole genome sequencing revealed an intronic biallelic mutation in the NDUFB7 gene (c.113-10C>G) and splicing pattern alterations in NDUFB7 mRNA were confirmed by RNA Sequencing. The detected variant resulted in a significant reduction of the NDUFB7 protein and reduced complex I activity. Complementation studies with expression of wild-type NDUFB7 in patient fibroblasts normalised complex I function. Here we report a case with a primary complex I defect due to a homozygous mutation in an intron region of the NDUFB7 gene. This article is protected by copyright. All rights reserved.
    Keywords:  Intrauterine clinical manifestations; NDUFB7; cryptic splice site mutation; isolated complex I deficiency; mitochondrial disease
    DOI:  https://doi.org/10.1002/humu.24173
  7. Biochim Biophys Acta Mol Basis Dis. 2021 Jan 21. pii: S0925-4439(21)00015-6. [Epub ahead of print] 166082
    Terburgh K, Coetzer J, Lindeque JZ, van der Westhuizen FH, Louw R.
      The dysfunction of respiratory chain complex I (CI) is the most common form of mitochondrial disease that most often presents as Leigh syndrome (LS) in children - a severe neurometabolic disorder defined by progressive focal lesions in specific brain regions. The mechanisms underlying this region-specific vulnerability to CI deficiency, however, remain elusive. Here, we examined brain regional respiratory chain enzyme activities and metabolic profiles in a mouse model of LS with global CI deficiency to gain insight into regional vulnerability to neurodegeneration. One lesion-resistant and three lesion-prone brain regions were investigated in Ndufs4 knockout (KO) mice at the late stage of LS. Enzyme assays confirmed significantly decreased (60-80%) CI activity in all investigated KO brain regions, with the lesion-resistant region displaying the highest residual CI activity (38% of wild type). A higher residual CI activity, and a less perturbed NADH/NAD+ ratio, correlate with less severe metabolic perturbations in KO brain regions. Moreover, less perturbed BCAA oxidation and increased glutamate oxidation seem to distinguish lesion-resistant from -prone KO brain regions, thereby identifying key areas of metabolism to target in future therapeutic intervention studies.
    Keywords:  Brain regions; Complex I deficiency; Leigh syndrome; Metabolomics; Mitochondrial disease; Ndufs4 knockout mice
    DOI:  https://doi.org/10.1016/j.bbadis.2021.166082
  8. Life (Basel). 2021 Jan 20. pii: E76. [Epub ahead of print]11(2):
    Zakirova EG, Muzyka VV, Mazunin IO, Orishchenko KE.
      The generally accepted theory of the genetic drift of mitochondrial alleles during mammalian ontogenesis is based on the presence of a selective bottleneck in the female germline. However, there is a variety of different theories on the pathways of genetic regulation of mitochondrial DNA (mtDNA) dynamics in oogenesis and adult somatic cells. The current review summarizes present knowledge on the natural mechanisms of mitochondrial genome elimination during mammalian development. We also discuss the variety of existing and developing methodologies for artificial manipulation of the mtDNA heteroplasmy level. Understanding of the basics of mtDNA dynamics will shed the light on the pathogenesis and potential therapies of human diseases associated with mitochondrial dysfunction.
    Keywords:  heteroplasmy; mitochondrial DNA segregation; mitochondrial engineered nucleases; mitophagy; selective elimination
    DOI:  https://doi.org/10.3390/life11020076