Wellcome Trust Centre For Mitochondrial Research

Monika Olahova

BiographyDr Monika Olahova

I am a post-doctoral research associate at the Wellcome Centre for Mitochondrial Research working with Prof. Robert Taylor. I am investigating the molecular pathology of novel mitochondrial disease genes identified by next generation sequencing technologies.

 

My interest in this research area stems from the potential to uncover key mechanistic elements underpinning the pathogenesis of mitochondrial disorders, thereby yielding important insights into the development of new treatments to improve the health and quality of life of patients with mitochondrial diseases.

Research Project

Principal Investigators: Professor Robert Taylor
Other staff members involved: Professor Zofia Chrzanowska-Lightowlers, Professor Robert Lightowlers, Professor Robert McFarland and Professor Rita Horvath.

Project Details

The main focus of our research is to understand fundamental regulatory mechanisms of mitochondrial transcription and translation in human disease.

The dominant role of mitochondria is energy production in the form of adenosine-5′-triphosphate via the respiratory chain in the process called oxidative phosphorylation (OXPHOS). Mutations of genes encoding OXPHOS proteins and RNAs are a significant contributor to human mitochondrial diseases.

The human exome harbours about 85% of disease-causing mutations. The recent advances in next generation, whole-exome sequencing is allowing us to identify novel mitochondrial disease-causing genes in patients with well-defined, multiple OXPHOS deficiencies indicative of a defect in generalised mitochondrial translation. I am investigating the molecular pathology of newly-identified mitochondrial disease genes by utilizing cells and tissues derived from patients to fully characterise the defective mitochondrial phenotype.

At present there are no highly effective treatments for patients with mitochondrial respiratory chain disease. However, we hope that an increased understanding of the basic mechanistic aspects of mitochondrial gene expression will make a positive step towards the development of therapeutic strategies to prevent and treat these devastating diseases.

Email: monika.olahova@ncl.ac.uk
Sponsor/Funder: The Wellcome Trust

Outcomes

Instability of the mitochondrial alanyl-tRNA synthetase underlies fatal infantile-onset cardiomyopathy. Sommerville EW, Zhou XL, Oláhová M, Jenkins J, Euro L, Konovalova S, Hilander T, Pyle A, He L, Habeebu S, Saunders C, Kelsey A, Morris AAM, McFarland R, Suomalainen A, Gorman GS, Wang ED, Thiffault I, Tyynismaa H, Taylor RW. Hum Mol Genet. 2019 Jan 15;28(2):258-268. doi: 10.1093/hmg/ddy294.

OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect. Thompson K, Mai N, Oláhová M, Scialó F, Formosa LE, Stroud DA, Garrett M, Lax NZ, Robertson FM, Jou C, Nascimento A, Ortez C, Jimenez-Mallebrera C, Hardy SA, He L, Brown GK, Marttinen P, McFarland R, Sanz A, Battersby BJ, Bonnen PE, Ryan MT, Chrzanowska-Lightowlers ZM, Lightowlers RN, Taylor RW. EMBO Mol Med. 2018 Nov;10(11). pii: e9060. doi: 10.15252/emmm.201809060.

Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function. Xu Z, Lo WS, Beck DB, Schuch LA, Oláhová M, Kopajtich R, Chong YE, Alston CL, Seidl E, Zhai L, Lau CF, Timchak D, LeDuc CA, Borczuk AC, Teich AF, Juusola J, Sofeso C, Müller C, Pierre G, Hilliard T, Turnpenny PD, Wagner M, Kappler M, Brasch F, Bouffard JP, Nangle LA, Yang XL, Zhang M, Taylor RW, Prokisch H, Griese M, Chung WK, Schimmel P. Am J Hum Genet. 2018 Jul 5;103(1):100-114. doi: 10.1016/j.ajhg.2018.06.006.

Defective mitochondrial protease LonP1 can cause classical mitochondrial disease. Peter B, Waddington CL, Oláhová M, Sommerville EW, Hopton S, Pyle A, Champion M, Ohlson M, Siibak T, Chrzanowska-Lightowlers ZMA, Taylor RW, Falkenberg M, Lightowlers RN. Hum Mol Genet. 2018 May 15;27(10):1743-1753. doi: 10.1093/hmg/ddy080.

Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease. Boczonadi V, King MS, Smith AC, Olahova M, Bansagi B, Roos A, Eyassu F, Borchers C, Ramesh V, Lochmüller H, Polvikoski T, Whittaker RG, Pyle A, Griffin H, Taylor RW, Chinnery PF, Robinson AJ, Kunji ERS, Horvath R. Genet Med. 2018 Oct;20(10):1224-1235. doi: 10.1038/gim.2017.251. Epub 2018 Mar 8.

Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder. Oláhová M, Yoon WH, Thompson K, Jangam S, Fernandez L, Davidson JM, Kyle JE, Grove ME, Fisk DG, Kohler JN, Holmes M, Dries AM, Huang Y, Zhao C, Contrepois K, Zappala Z, Frésard L, Waggott D, Zink EM, Kim YM, Heyman HM, Stratton KG, Webb-Robertson BM; Undiagnosed Diseases Network, Snyder M, Merker JD, Montgomery SB, Fisher PG, Feichtinger RG, Mayr JA, Hall J, Barbosa IA, Simpson MA, Deshpande C, Waters KM, Koeller DM, Metz TO, Morris AA, Schelley S, Cowan T, Friederich MW, McFarland R, Van Hove JLK, Enns GM, Yamamoto S, Ashley EA, Wangler MF, Taylor RW, Bellen HJ, Bernstein JA, Wheeler MT. Am J Hum Genet. 2018 Mar 1;102(3):494-504. doi: 10.1016/j.ajhg.2018.01.020. Epub 2018 Feb 22.

Using a quantitative quadruple immunofluorescent assay to diagnose isolated mitochondrial Complex I deficiency. Ahmed ST, Alston CL, Hopton S, He L, Hargreaves IP, Falkous G, Oláhová M, McFarland R, Turnbull DM, Rocha MC, Taylor RW. Sci Rep. 2017 Nov 15;7(1):15676. doi: 10.1038/s41598-017-14623-2.

Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies. Feichtinger RG, Oláhová M, Kishita Y, Garone C, Kremer LS, Yagi M, Uchiumi T, Jourdain AA, Thompson K, D’Souza AR, Kopajtich R, Alston CL, Koch J, Sperl W, Mastantuono E, Strom TM, Wortmann SB, Meitinger T, Pierre G, Chinnery PF, Chrzanowska-Lightowlers ZM, Lightowlers RN, DiMauro S, Calvo SE, Mootha VK, Moggio M, Sciacco M, Comi GP, Ronchi D, Murayama K, Ohtake A, Rebelo-Guiomar P, Kohda M, Kang D, Mayr JA, Taylor RW, Okazaki Y, Minczuk M, Prokisch H. Am J Hum Genet. 2017 Oct 5;101(4):525-538. doi: 10.1016/j.ajhg.2017.08.015. Epub 2017 Sep 21.

Pathogenic variants in HTRA2 cause an early-onset mitochondrial syndrome associated with 3-methylglutaconic aciduria. Oláhová M, Thompson K, Hardy SA, Barbosa IA, Besse A, Anagnostou ME, White K, Davey T, Simpson MA, Champion M, Enns G, Schelley S, Lightowlers RN, Chrzanowska-Lightowlers ZM, McFarland R, Deshpande C, Bonnen PE, Taylor RW. J Inherit Metab Dis. 2017 Jan;40(1):121-130. doi: 10.1007/s10545-016-9977-2. Epub 2016 Sep 30.

Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype. Alston CL, Compton AG, Formosa LE, Strecker V, Oláhová M, Haack TB, Smet J, Stouffs K, Diakumis P, Ciara E, Cassiman D, Romain N, Yarham JW, He L, De Paepe B, Vanlander AV, Seneca S, Feichtinger RG, Płoski R, Rokicki D, Pronicka E, Haller RG, Van Hove JL, Bahlo M, Mayr JA, Van Coster R, Prokisch H, Wittig I, Ryan MT, Thorburn DR, Taylor RW. Am J Hum Genet. 2016 Jul 7;99(1):217-27. doi: 10.1016/j.ajhg.2016.05.021. Epub 2016 Jun 30.

A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype.

Alston CL, Howard C, Oláhová M, Hardy SA, He L, Murray PG, O’Sullivan S, Doherty G, Shield JP, Hargreaves IP, Monavari AA, Knerr I, McCarthy P, Morris AA, Thorburn DR, Prokisch H, Clayton PE, McFarland R, Hughes J, Crushell E, Taylor RW. J Med Genet. 2016 Sep;53(9):634-41. doi: 10.1136/jmedgenet-2015-103576. Epub 2016 Apr 18.

LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population.

Oláhová M, Hardy SA, Hall J, Yarham JW, Haack TB, Wilson WC, Alston CL, He L, Aznauryan E, Brown RM, Brown GK, Morris AA, Mundy H, Broomfield A, Barbosa IA, Simpson MA, Deshpande C, Moeslinger D, Koch J, Stettner GM, Bonnen PE, Prokisch H, Lightowlers RN, McFarland R, Chrzanowska-Lightowlers ZM, Taylor RW. Brain. 2015 Dec;138(Pt 12):3503-19. doi: 10.1093/brain/awv291. Epub 2015 Oct 27.

A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency. Alston CL, Ceccatelli Berti C, Blakely EL, Oláhová M, He L, McMahon CJ, Olpin SE, Hargreaves IP, Nolli C, McFarland R, Goffrini P, O’Sullivan MJ, Taylor RW. Hum Genet. 2015 Aug;134(8):869-79. doi: 10.1007/s00439-015-1568-z. Epub 2015 May 26.

A peroxiredoxin, PRDX-2, is required for insulin secretion and insulin/IIS-dependent regulation of stress resistance and longevity. Oláhová M, Veal EA. Aging Cell. 2015 Aug;14(4):558-68. doi: 10.1111/acel.12321. Epub 2015 Mar 23.

A truncating PET100 variant causing fatal infantile lactic acidosis and isolated cytochrome c oxidase deficiency. Oláhová M, Haack TB, Alston CL, Houghton JA, He L, Morris AA, Brown GK, McFarland R, Chrzanowska-Lightowlers ZM, Lightowlers RN, Prokisch H, Taylor RW. Eur J Hum Genet. 2015 Jul;23(7):935-9. doi: 10.1038/ejhg.2014.214. Epub 2014 Oct 8.

Genome-wide screening identifies new genes required for stress-induced phase 2 detoxification gene expression in animals. Crook-McMahon HM, Oláhová M, Button EL, Winter JJ, Veal EA. BMC Biol. 2014 Aug 14;12:64. doi: 10.1186/s12915-014-0064-6.

Translating a low-sugar diet into a longer life by maintaining thioredoxin peroxidase activity of a peroxiredoxin. Veal EA, Oláhová M. Mol Cell. 2011 Sep 2;43(5):699-701. doi: 10.1016/j.molcel.2011.08.016.

A redox-sensitive peroxiredoxin that is important for longevity has tissue- and stress-specific roles in stress resistance. Oláhová M, Taylor SR, Khazaipoul S, Wang J, Morgan BA, Matsumoto K, Blackwell TK, Veal EA. Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19839-44. doi: 10.1073/pnas.0805507105. Epub 2008 Dec 8.

Effect of selenium on lipid alternations in pigment-forming yeasts. Certík, M., Breierová, E., Oláhová, M., Sajbidor, J. and Márová, Food Science and Biotechnology. 2013;22:45-51.