What are we studying?

The main focus of our research is set on mitochondrial deficiencies. Malfunction of mitochondria primarily affect tissues with intensive metabolism and high oxygen expenditure. Consequently, mitochondrial dysfunctions also play major roles in chronic neurodegenerative diseases. Our goal is to gain insights into the above processes. We examine various compounds for their potential beneficial effects on selected defects of the mitochondrial electron transport chain. Such a compound is methylene blue, which can partially restore mitochondrial parameters, including the metabolic flux in the Krebs cycle, in case of Complex I and Complex III deficiencies; this eventually improves the viability of neurons. A key player in the Krebs cycle is the α-ketoglutarate dehydrogenase enzyme complex (KGDHc). Mechanistically cognate enzymes like the pyruvate dehydrogenase complex, branched-chain α-keto acid dehydrogenase complex and α-ketoadipate dehydrogenase complex are other members of the α-keto acid dehydrogenase family. Under pathologically relevant conditions, the above complexes all produce reactive oxygen species (ROS) that may contribute to the progression of various neurological pathologies. One of our main objectives is to shed light on the structural and mechanistic bases of this ROS production and potentially design drug candidate molecules.

How do we research?

In our laboratory, the recombinant enzyme complexes, their disease-causing variants (mutants) and the respective subunits are examined via the following methods.

Structural analysis:

  • cryo-EM, HDX-MS, X-ray crystallography, CD spectropolarimetry, NMR spectroscopy, nano-LC MS

Functional analysis:

  • enzyme kinetics, ROS production assays, bioenergetic analysis (on patient-derived fibroblasts and mutant cell lines)

Who are we?

Dr. Attila Ambrus graduated as a Chemist in 1996. In the same year, he started his Ph.D. work in the Department of Biochemistry and Molecular Biology at the University of Debrecen. During his Ph.D. studies, he also obtained an Advanced Certificate at the University of London (Principles of Protein Structure). Having won several research fellowships, he participated in study tours that took him to Jena, Arizona, Pittsburgh and New Jersey, among other places. Even nowadays, he is still an active associate of the international scientific community: he is the member of the Protein Society, European Society for Neurochemistry and American Chemical Society. He has been working at the Semmelweis University since 2006. Currently, he is an Associate Professor at the Department of Biochemistry.

Current research projects

  • Structure elucidation of seven disease-causing variants of the human lipoamide dehydrogenase
  • Glutamate toxicity mediated by mitochondria
  • Structure elucidation of seven disease-causing variants of the human lipoamide dehydrogenase

Staff members and publications

PhD students

  • Éva Nemes-Nikodém
  • Bálint Nagy
  • Gergely Sváb
  • Melinda Zsófia Zámbó

TDK students

  • Gu Yibo
  • Mária Judit Kirchlechner-Farkas
  • Márton Kokas
  • Virág Kovács
  • Adrienn Nagy
  • Krisztina Rubina Vass (BME)

Significant international collaborators