Nucleotide homeostasis and mitochondrial function: physiological and therapeutic implications

VHIR is seeking an outstanding and highly motivated postdoctoral researcher to apply for a Marie Sklodowska-Curie Postdoctoral Fellowship and join the Neuromuscular and Mitochondrial Disorders Research Group.

Marie Skłodowska-Curie Actions – Postdoctoral Fellowships (MSCA-PF)

The Marie Skłodowska-Curie Postdoctoral Fellowships (MSCA-PF) are part of the Horizon Europe programme and support postdoctoral researchers in developing an original research and innovation project through international mobility.

The programme aims to strengthen researchers’ careers through excellent science, international collaboration and interdisciplinary experience, while fostering integration in both academic and non-academic environments. The MSCA-PF call is highly competitive and represents an excellent opportunity to attract international talent and support researchers in consolidating their scientific careers through an ambitious mobility-based fellowship.

The 2026 call closes on 09/09/2026 (17:00 Brussels time). For candidates applying to a European Postdoctoral Fellowship, the fellowship duration is from 12 to 24 months.

Full eligibility details: MSCA Postdoctoral Fellowships 2026

Background

Mitochondrial DNA (mtDNA) depletion/deletions syndromes (MDDS) are severe conditions caused by mutations in nuclear genes involved in mtDNA replication. dNTP imbalances are often associated to these disorders, either because the primary gene is involved in dNTP anabolic or catabolic pathways, or because the mtDNA aberrations secondarily alter dNTP metabolism.

The dNTP homeostasis is a therapeutic target for some MDDS. For instance, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by the toxic accumulation of thymidine and deoxyuridine, and the treatments of this disorder aim to clear the overload of these metabolites. Also, the recent approval of thymidine and deoxycytidine to treat TK2 deficiency (Kigevvy™) constitutes the first therapy that changes the natural history of an MDDS form, extending the life expectancy of patients that otherwise would die in months or few years.

Preclinical studies support the notion that stimulating mtDNA replication by enhancing dNTP synthesis may be an effective treatment of other MDDS forms. Moreover, our recent demonstration of dGTP binding the OXPHOS complex I constitutes a novel finding with potential unexplored functional consequences. Therefore, the mitochondrial dNTP metabolism and how it is linked to the OXPHOS function and the mitochondrial disorders is currently a hot topic. Improving our knowledge in this field may result in therapies for devastating disorders with no effective treatment so far.

Objective

The general objective of this action is to investigate so far unexplored aspects of the dNTP metabolism in the context of the mitochondrial (dys)function, with especial focus on mtDNA replication and maintenance, including the investigation and further development of potential therapies for mtDNA maintenance disorders.

Examples of some specific objectives:

• To identify genetic/protein/metabolic factors determining mitochondrial dNTP homeostasis and their relation with normal and dysfunctional mtDNA replication.
• To study dNTP homeostasis in several in vitro and in vivo models of mtDNA replication defects, and to design/test therapy strategies to modulate dNTP imbalances.
• To explore novel potential dNTP-related therapy targets, such as nucleoside/nucleotide transport or enzyme activation/inhibition.
• To contribute to preclinical/clinical development of ongoing therapies, such as AAV-based gene therapy for MNGIE and other dNTP-related therapies in their track to the regulatory approval.

Beyond these examples, the details of the project will be finally re-designed according to the expertise of the candidate and will be jointly re-shaped once he/she is integrated in the research group.

Our Group

The research group of neuromuscular and mitochondrial disorders focuses its research activity on studying the pathophysiological mechanisms of mitochondrial diseases, especially those associated with defects in mtDNA maintenance. In addition, we have some research lines dedicated to the study of another group of metabolic disorders, the muscle glycogenosis. Some of our current research lines are:

• Study of the pathomechanisms of MDDS and development of therapeutic strategies for them.
• Pathophysiology of mitochondrial diseases due to defects in mitochondrial translation.
• AAV-based gene therapy (for MNGIE disease and for mutations in GFM1).
• Pathomechanisms of the McArdle's disease using a murine model of this disorder.
• Coordination of EUROMAC (European registry of patients with McArdle's disease and other glycogenosis).

Main responsibilities and duties:

• Work with cellular and mouse models (available mouse strains genetically modified in the following genes: Polg, Tk2, Dguok, Opa1, Tymp/Upp1, Ndufa10, Pygm).
• The methodology will comprise, among other techniques, general molecular biology methods, real-time qPCR, digital PCR, enzymology-linked methods, dNTP assessment, targeted metabolomics (HPLC-mass spectrometry).
• In addition, the VHIR core facilities offer well-equipped platforms: genomics, molecular diagnosis, cytometry, microscopy.