bims-cytox1 2021-04-18 papers

Issue of 2021–04–18
three papers selected by
Gavin McStay, Staffordshire University

Neuromuscul Disord. 2021 Mar 03. pii: S0960-8966(21)00064-X. [Epub ahead of print]

A novel nonsense variant in MT-CO3 causes MELAS syndrome.

Wei Wang, Yuan Sun, Yan Lin, Xuebi Xu, Dandan Zhao, Kunqian Ji, Wei Li, Yuying Zhao, Chuanzhu Yan.

Both mitochondrial and nuclear gene mutations can cause cytochrome c oxidase (COX, complex Ⅳ) dysfunction, leading to mitochondrial diseases. Although numerous diseases caused by defects of the COX subunits or COX assembly factors have been documented, clinical cases directly related to mitochondrial cytochrome c oxidase subunit 3 gene (MT-CO3) mutations are relatively rare. Here, we report a 47-year-old female patient presented with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Muscle pathology revealed ragged-red fibres and remarkable COX-deficient muscle fibres. Muscle mitochondrial DNA sequencing analysis identified a novel MT-CO3 variant (m.9553G>A) that changed a highly conserved amino acid to a stop codon (p.Trp116*). This variant was heteroplasmic in multiple tissues, where the mutation load was 13% in oral epithelial cells, 89% in muscle samples, and not detectable in the peripheral blood lymphocytes. Single muscle fiber PCR analysis showed clear segregation of the mutation load with COX deficient fibres. Western blot analysis of the muscle samples revealed a significant decrease in the levels of COX1, COX2, COX3, COX4 and UQCRC2. COX respiration activity was remarkably reduced (58.84%) relative to the controls according to spectrophotometric assays. Taken together, our results indicated that this m.9553G>A variant may be responsible for the MELAS symdrome in the proband by affecting the stability and function of COX. The study expands the clinical and molecular spectrum of COX3-specific mitochondrial diseases.

Keywords: Cytochrome c oxidase; Heteroplasmy; MELAS; MT-COX3; m.9553G>A

DOI: https://doi.org/10.1016/j.nmd.2021.02.020

Cell Rep. 2021 Apr 13. pii: S2211-1247(21)00277-1. [Epub ahead of print]35(2): 108963

A membrane arm of mitochondrial complex I sufficient to promote respirasome formation.

Hezhi Fang, Xianglai Ye, Jie Xie, Yuanyuan Li, Haiyan Li, Xinzhu Bao, Yue Yang, Zifan Lin, Manli Jia, Qing Han, Jingjing Zhu, Xueyun Li, Qiongya Zhao, Yanling Yang, Jianxin Lyu.

The assembly pathways of mitochondrial respirasome (supercomplex I+III2+IV) are not fully understood. Here, we show that an early sub-complex I assembly, rather than holo-complex I, is sufficient to initiate mitochondrial respirasome assembly. We find that a distal part of the membrane arm of complex I (PD-a module) is a scaffold for the incorporation of complexes III and IV to form a respirasome subcomplex. Depletion of PD-a, rather than other complex I modules, decreases the steady-state levels of complexes III and IV. Both HEK293T cells lacking TIMMDC1 and patient-derived cells with disease-causing mutations in TIMMDC1 showed accumulation of this respirasome subcomplex. This suggests that TIMMDC1, previously known as a complex-I assembly factor, may function as a respirasome assembly factor. Collectively, we provide a detailed, cooperative assembly model in which most complex-I subunits are added to the respirasome subcomplex in the lateral stages of respirasome assembly.

Keywords: Leigh syndrome; TIMMDC1; cooperative assembly; mitochondrial respirasome; oxidative phosphorylation

DOI: https://doi.org/10.1016/j.celrep.2021.108963

J Inherit Metab Dis. 2021 Apr 14.

Metabolic impact of pathogenic variants in the mitochondrial glutamyl-tRNA synthetase EARS2.

Min Ni, Lauren Friedrich, Chunxiao Pan, Hieu Vu, Jimin Pei, Bookyung Ko, Ling Cai, Ashley Solmonson, Chendong Yang, Kimberly M Nugent, Nick V Grishin, Chao Xing, Elizabeth Roeder, Ralph J DeBerardinis.

Glutamyl-tRNA synthetase 2 (encoded by EARS2) is a mitochondrial aminoacyl-tRNA synthetase required to translate the 13 subunits of the electron transport chain encoded by the mitochondrial DNA. Pathogenic EARS2 variants cause combined oxidative phosphorylation deficiency, subtype 12 (COXPD12), an autosomal recessive disorder involving lactic acidosis, intellectual disability and other features of mitochondrial compromise. Patients with EARS2 deficiency present with variable phenotypes ranging from neonatal lethality to a mitigated disease with clinical improvement in early childhood. Here, we report a neonate homozygous for a rare pathogenic variant in EARS2 (c.949G>T; p.G317C). Metabolomics in primary fibroblasts from this patient revealed expected abnormalities in TCA cycle metabolites, as well as numerous changes in purine, pyrimidine and fatty acid metabolism. To examine genotype-phenotype correlations in COXPD12, we compared the metabolic impact of reconstituting these fibroblasts with wild-type EARS2 vs. four additional EARS2 variants from COXPD12 patients with varying clinical severity. Metabolomics identified a group of signature metabolites, mostly from the TCA cycle and amino acid metabolism, that discriminate between EARS2 variants causing relatively mild and severe COXPD12. Taken together, these findings indicate that metabolomics in patient-derived fibroblasts may help establish genotype-phenotype correlations in EARS2 deficiency and likely other mitochondrial disorders. This article is protected by copyright. All rights reserved.

Keywords: EARS2; Mitochondria; genotype-phenotype correlation; inborn errors of metabolism; lactic acidosis; metabolomics

DOI: https://doi.org/10.1002/jimd.12387