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Molecular pathogenesis of mitochondrial OXPHOS diseases


Nuclear and mitochondrial genetic variants and molecular bases of mitochondrial OXPHOS diseases

Tech Area / Field

  • BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology
  • BIO-CHM/Biochemistry/Biotechnology
  • BIO-INF/Bioinformatics/Biotechnology
  • MED-DID/Diagnostics & Devices/Medicine

8 Project completed

Registration date

Completion date

Senior Project Manager
Turebayev A

Leading Institute
Center of Medical Genetics of NAS RA, Armenia, Yerevan

Supporting institutes

  • National Bureau of Expertises / National Academy of Sciences of the Republic of Armenia, Armenia, Yerevan\nAkhali Sitsotskhle LLC, Georgia, Tbilisi


  • National Institute of Neuroscience, NCNP, Japan, Tokyo\nNewcastle University / Wellcome Trust Center for Mitochondrial, UK, Newcastle upon Tyne\nKennedy Center / Copenhagen University Hospital, Denmark, Glostrup

Project summary

Current status. Mitochondrial dysfunction is at the core of a surprising range of both common and rare disorders opening a promising new avenue for their treatment. As the mitochondria are responsible for energy production, key sources of oxidative stress, central in many other aspects of well-being/survival of cells, and regulate apoptosis and calcium homeostasis, any disease could theoretically be related to mitochondrial defect. Mitochondrial oxidative phosphorylation (OXPHOS) diseases represent a challenging class of disorders that are greatly under-recognized, clinically heterogenous, and are thought to affect roughly 1:4000 people. OXPHOS diseases are classified as either those due to mutations in mitochondrial DNA (mtDNA) or disorders due to mutations in nuclear DNA (nDNA). mtDNA accounts only for 15% of all primary childhood cases; the remaining are mostly recessive alleles of more than 80 nuclear genes. Thanks to recent whole-exome sequencing studies several unexpected molecular aetiologies have been revealed for mitochondrial disease phenotype. However, the known disease genes likely account for only a small fraction of the total genetic burden of OXPHOS diseases. More than 1000 nuclear genes encoding mitochondrial proteins represent strong candidates for OXPHOS diseases. There remain many gaps in knowledge of the overall frequency, full spectrum, and long-term natural history of these disorders. Another major question of mitochondrial diseases is the pathogenesis of these disorders caused by mutations of perse groups of genes. Clinical classification is still laborious, and the diagnosis of these disorders is inconclusive.
The Project aim. The impact of nuclear and mitochondrial genetic variants on the molecular pathogenecity and underlying cellular dysfunction of mitochondrial OXPHOS diseases is the major objective of this study on the way to determine the molecular bases of these deficiencies. To contribute to the solution of the general question of the proposal, we will study a multiethnic group of more than 100 patients with primary mitochondrial diseases, both sporadic and familial, based on biochemical assessment, and respective number of ethnically-matched healthy controls. This project will be the first to study in depth the prevalence and incidence of OXPHOS diseases in Armenia and Georgia. Having in question the extensive locus heterogeneity, allelic heterogeneity, and pleiotropy of OXPHOS diseases with the availability of more than 1000 strong candidate genes encoding the mitochondrial proteome, targeted Next-Generation Sequencing (NGS) analysis combined with cell functional analysis will be applied for the solution of the mentioned research questions of mitochondrial disease. Given the general question of the proposal, the following specific objectives are:
1) discover and elucidate the role of single nucleotide variants (SNVs) and small insertion/deletion variants (indels) and corresponding genes related to mitochondrial OXPHOS diseases by targeted NGS analysis in patients in whom no genetic explanation has been found,
2) clarify the burden of known and new rare mutations and establish a database of nDNA and mtDNA mutations related to mitochondrial OXPHOS diseases in the selected populations,
3) decipher a “mitochondrial defect map” to reveal underlying mechanisms of mitochondrial dysfunction observed in patients harboring newly discovered genetic changes,
4) justify the clinical classification for accurate diagnosis and prognostic counseling of mitochondrial OXPHOS diseases to discriminate between perse states of OXPHOS diseases by phenotype/genotype correlation analysis.
The project’ influence on progress in this area. The findings will be connected with one of the most actual problems of molecular medicine in the identification of genes responsible for the development of genetically influenced diseases. The project will explore new genetic causes and their future diagnostic application, including preimplantation genetic diagnosis. Results will broaden understanding on the relationship of the genotype to the disease clinical picture, which will be used as a prototype for prospective large-scale studies. Investigation of the molecular mechanism in mitochondrial defects will give new general insight into how the mitochondrial mechanisms are modified under mitochondrial defect, not just when it is a primary mitochondrial disease, but also when the disease is genetically nuclear and gives secondary mitochondrial defect. Therefore such results will give great knowledge not only to understand mitochondrial myopathies, but also give important insight into some of the big neurological diseases where mitochondrial has already been shown to be involved in the disease mechanism. And knowledge from this project may open new treatment possibilities using mitochondria-targeting as a primary treatment strategy.
The participants’ expertise. Inpidual participants of different categories from Armenia and Georgia are working in medical genetic and molecular biology research, diagnostics, and treatment, and have many years of working experience in different international research projects and institutions. They have strong skilled-experience in all the techniques and methods which will be applied during the course of the project. Main participants are co-authors of several publications in genetics (please, see attached “Supporting Information”). All participants of this regional project are selected not only on the bases of their outstanding professional experience in medicine and medical genetics, but also based on the fact that they are representing the institutions which are daily facing with the problems connected with diagnosis, treatment, and prognosis of patients with mitochondrial diseases in their countries.
Expected results and their application. The categories of technology development of the research proposal correspond to basic and applied research. The project will undoubtedly identify new candidate genes, and will elucidate their role in pathogenecity of OXPHOS diseases. Research results will establish the molecular mechanisms of mitochondrial disease and elucidate the complex relationships between genotypes and perse clinical phenotypes associated with these disorders. Genotype-phenotype analysis will ascertain the molecular aetiology of new mitochondrial OXPHOS conditions which will be taken into account in clinical diagnosis. The applying strategy of prioritized targeted exome-sequencing approach will bring out new mutations which pathogenecity and role in causality of mitochondrial diseases will be unmasked by cell functional analysis. Targeted NGS approach will be adopted in genetic diagnosis of mitochondrial OXPHOS diseases in participating countries which will facilitate molecular diagnosis, and allow the identification of more number of patients with mitochondrial disorders. This will resolve some of the open issues emerging from clinical practice in this field, including difficulties in diagnosing the conditions and in providing adequate counseling, and unpredictable prognoses. Elucidating the pathogenesis of mitochondrial disorders will undoubtedly uncover novel protein targets or molecular pathways that may be exploited for therapy development.
Meeting ISTC goals and objectives. The scientists and the specialists connected with weapon will have the opportunity for reorientation of the capabilities aimed to peaceful activities for the implementation of the aims and problems of ISTC. There will be huge support to basic and applied research in peaceful aims. The project will promote to the solution of national, regional, and international scientific problems, wide involvement of scientists and participating institutions into international scientific community through providing project results during international scientific events, and will have a huge impact on the population, environment and for the promotion of national and international public health problems.
Scope of activities. The study consists of seven major parallel and consecutive stages: 1) selection of patients and controls, creation of biobank, 2) targeted exome-sequencing of selected genes of mitochondrial and nuclear genome in all cases, 3) homozygosity analysis of detected nuclear genome sequence variants, 4) in silico and phylogenetic analyses of detected DNA sequence variants, 5) genotyping of discovered variants among healthy controls, 6) cell functional analysis of detected DNA sequence variants, and 7) phenotype/genotype correlation analysis. To clarify the burden of relatively rare mutations of mitochondrial and nuclear genome, we will perform targeted exome-sequencing of known and candidate nuclear and mitochondrial genes in patients. Following homozygosity analysis, in silico exon-skipping analysis, and phylogenetic analysis we will ascertain the deleterious variants of mtDNA and nDNA which later will be screened among healthy population controls by genotyping analysis. Functional analysis of detected DNA sequence variants will involve research of cDNA with a) direct Sanger-sequencing, and b) cell functional analysis to assess the role of wild-type variants on rescue of protein production/activity, and to evaluate the different mitochondrial regulatory pathways before and after transduction of patients’ cells with normal cDNA. Finally, to match the disease clinical picture with the relevant genotype, and to predict the course of the severity of the disease, we will perform phenotype/genotype correlation analysis incorporating the data of clinical, genomic, bioinformatics, and functional research.
Role of Foreign Collaborators/Partners. The foreign collaborators are outstanding scientists and experts in the field of mitochondrial disorders and modern genomic technologies. Dr. Y. Goto, the director of the Department of Mental Retardation and Birth Defect Research of National Institute of Neuroscience (Japan) is studying the biological bases of neurodevelopmental disorders in children, including mitochondrial diseases. Prof. Z. Tümer is the head of R&D of Applied Human Molecular Genetics, Kennedy Center (Denmark) working on complex neuropsychiatric disorders, including mitochondrial defects. Prof. R. Taylor is leading the National-Commissioned Highly Specialised Mitochondrial Diagnostic laboratory at the Wellcome Trust Centre for Mitochondrial Research (the UK) integrates programme of basic and clinical mitochondrial disease research. They have expressed their willingness to provide exchange of information, cross-check of results, joint seminars, workshops, meetings, and publication, sharing of samples, as well as provide equipment during the visits of the project participants in their labs.
Technical approach and methodology. The key to success of the project’s methodology is the combination of state-of-the-art approaches and technologies of modern genomics with cellular models of the disease through molecular biology and bioinformatics which could eventually establish pathogenecity of novel mutations in inpidual cases of mitochondrial syndromes, and spread light on mitochondrial dysfunction . Because the majority of cases are sporadic with phenotypic persity of syndromes, a standard approach of whole-exome sequencing is not applicable for research of such diseases. Our approach is a targeted exome-sequencing of nuclear and mitochondrial genes based on their functional involvement in mitochondrial function and prediction of deleterious nature of mutations in synergy with cellular functional analyses which will discover the pathogenic role of several candidate genes.


The International Science and Technology Center (ISTC) is an intergovernmental organization connecting scientists from Kazakhstan, Armenia, Tajikistan, Kyrgyzstan, and Georgia with their peers and research organizations in the EU, Japan, Republic of Korea, Norway and the United States.


ISTC facilitates international science projects and assists the global scientific and business community to source and engage with CIS and Georgian institutes that develop or possess an excellence of scientific know-how.

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