bims-cytox1 2019-12-01 papers

Issue of 2019–12–01
four papers selected by
Gavin McStay, Staffordshire University

J Neurol. 2019 Nov 27.

Leber hereditary optic neuropathy plus dystonia, and transverse myelitis due to double mutations in MT-ND4 and MT-ND6.

Andres Berardo, Valentina Emmanuele, Wendy Vargas, Kurenai Tanji, Ali Naini, Michio Hirano.

Leber hereditary optic neuropathy (LHON) typically presents as painless central or centrocecal scotoma and is due to maternally inherited mitochondrial DNA (mtDNA) mutations. Over 95% of LHON cases are caused by one of three mtDNA "common" point mutations: m.3460G>A, m.11778G>A, or m.14484T>C, which are all in genes encoding structural subunits of complex I of the respiratory chain. Intriguing features of LHON include: incomplete penetrance, tissue specificity, and male predominance, indicating that additional genetic or environmental factors are modulating the phenotypic expression of the pathogenic mtDNA mutations. However, since its original description as a purely ophthalmological disorder, LHON has also been linked to multisystemic conditions with variable neurological, cardiac, and skeletal abnormalities. Although double "common" mutations have been reported to cause LHON and LHON-plus, they are extremely rare. Here, we present a patient with an unusual double point mutation (m.11778 G>A and m.14484T>C) with a multisystemic LHON-plus phenotype characterized by: optic neuropathy, ptosis, ataxia, dystonia, dysarthria, and recurrent extensive transverse myelitis.

Keywords: Dystonia; Leber hereditary optic neuropathy; Mitochondrial DNA; Mutation; Transverse myelitis

DOI: https://doi.org/10.1007/s00415-019-09619-z

Biochem Soc Trans. 2019 Nov 26. pii: BST20191042. [Epub ahead of print]

Cellular mechanisms of complex I-associated pathology.

Andrey Y Abramov, Plamena R Angelova.

Mitochondria control vitally important functions in cells, including energy production, cell signalling and regulation of cell death. Considering this, any alteration in mitochondrial metabolism would lead to cellular dysfunction and the development of a disease. A large proportion of disorders associated with mitochondria are induced by mutations or chemical inhibition of the mitochondrial complex I - the entry point to the electron transport chain. Subunits of the enzyme NADH: ubiquinone oxidoreductase, are encoded by both nuclear and mitochondrial DNA and mutations in these genes lead to cardio and muscular pathologies and diseases of the central nervous system. Despite such a clear involvement of complex I deficiency in numerous disorders, the molecular and cellular mechanisms leading to the development of pathology are not very clear. In this review, we summarise how lack of activity of complex I could differentially change mitochondrial and cellular functions and how these changes could lead to a pathology, following discrete routes.

Keywords: Introduction; bioenergetics; calcium; complex I; mitochondria; reactive oxygen species

DOI: https://doi.org/10.1042/BST20191042

Neuropediatrics. 2019 Nov 28.

Biallelic Mutations in MTPAP Associated with a Lethal Encephalopathy.

Lien Van Eyck, Francesco Bruni, Anne Ronan, Tracy A Briggs, Tony Roscioli, Gillian I Rice, Grace Vassallo, Mathieu P Rodero, Langping He, Robert W Taylor, John H Livingston, Zofia M A Chrzanowska-Lightowlers, Yanick J Crow.

BACKGROUND: A homozygous founder mutation in MTPAP/TENT6, encoding mitochondrial poly(A) polymerase (MTPAP), was first reported in six individuals of Old Order Amish descent demonstrating an early-onset, progressive spastic ataxia with optic atrophy and learning difficulties. MTPAP contributes to the regulation of mitochondrial gene expression through the polyadenylation of mitochondrially encoded mRNAs. Mitochondrial mRNAs with severely truncated poly(A) tails were observed in affected individuals, and mitochondrial protein expression was altered.
OBJECTIVE: To determine the genetic basis of a perinatal encephalopathy associated with stereotyped neuroimaging and infantile death in three patients from two unrelated families.
METHODS: Whole-exome sequencing was performed in two unrelated patients and the unaffected parents of one of these individuals. Variants and familial segregation were confirmed by Sanger sequencing. Polyadenylation of mitochondrial transcripts and de novo synthesis of mitochondrial proteins were assessed in patient's fibroblasts.
RESULTS: Compound heterozygous p.Ile428Thr and p.Arg523Trp substitutions in MTPAP were recorded in two affected siblings from one family, and a homozygous p.Ile385Phe missense variant identified in a further affected child from a second sibship. Mitochondrial poly(A) tail analysis demonstrated shorter posttranscriptional additions to the mitochondrial transcripts, as well as an altered expression of mitochondrial proteins in the fibroblasts of the two siblings compared with healthy controls.
CONCLUSION: Mutations in MTPAP likely cause an autosomal recessive perinatal encephalopathy with lethality in the first year of life.

DOI: https://doi.org/10.1055/s-0039-3400979

FEBS Lett. 2019 Nov 25.

The Mgr2 subunit of the TIM23 complex regulates membrane insertion of marginal stop-transfer signals in the mitochondrial inner membrane.

Seoeun Lee, Hunsang Lee, Suji Yoo, Raffaele Leva, Marin van der Laan, Gunnar von Heijne, Hyun Kim.

The TIM23 complex mediates membrane insertion of presequence-containing mitochondrial proteins via a stop-transfer mechanism. Stop-transfer signals consist of hydrophobic transmembrane segments and flanking charges. Mgr2 functions as a lateral gatekeeper of the TIM23 complex. However, it remains elusive which features of stop-transfer signals are discriminated by Mgr2. To determine the effects of Mgr2 on the TIM23-mediated stop-transfer pathway, we measured membrane insertion of model transmembrane segments of varied hydrophobicity and flanking charges in Mgr2-deletion or -overexpression yeast strains. We found that upon deletion of Mgr2, the threshold hydrophobicity for membrane insertion, as well as the requirement for matrix-facing positive charges, is reduced. These results imply that the Mgr2-mediated gatekeeper function is important for controlling membrane sorting of marginal stop-transfer signals.

Keywords: Hydrophobicity; Mgm1; TIM23; import; yeast

DOI: https://doi.org/10.1002/1873-3468.13692