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Lecture "Treatment options for mitochondrial disorders"

RNDr. Tomáš Mráček, PhD, Laboratory of Bioenergetics, IPHYS

Mitochondrial disorders are among the most common inborn errors of metabolism. As a group, they exhibit enormous genetic and clinical heterogeneity - they can occur at any age, present with various phenotypes affecting any organ, and with any mode of inheritance. What mitochondrial diseases have in common is a disruption of the activity of the respiratory chain, which is responsible for more than 90% of energy production in cells. While the diagnosis of mitochondrial disorders has been accelerated in recent years by the introduction of next-generation sequencing techniques, treatment options are still very limited. For many patients, only supportive or symptomatic therapy is available. However, decades of basic and preclinical research have uncovered potential targets and many compounds or interventions are now in clinical trials.

Our work focuses on mitochondrial diseases caused by ATP synthase dysfunction.  Genetically, these are mainly caused by mutations in the assembly factor TMEM70. Over the years, we have developed several animal models of Tmem70 deficiency that have allowed us to unravel potential therapeutic options. We found that a ketogenic diet significantly improved lifespan and attenuated the biochemical defect in a mouse model of TMEM70 deficiency. Interestingly, it not only improved the metabolic phenotype, but also directly led to an increase in the level of assembled ATP synthase holoenzyme in the liver. In addition, the rat model allowed us to test the feasibility of gene therapy using a transgenic rescue approach. EF-1α-driven tgTmem70 expression in knockout animals (SHR-Tmem70ko/ko,tg/tg) resulted in fully viable offspring despite only partial restoration (16-49%) of TMEM70 levels. Still, this was sufficient for full biochemical complementation in the liver and heart. In conclusion, animal models are an important tool to unravel the nature of TMEM70 deficiency in humans.



Tomáš Mráček, PhD (H-index 24) is the head of Laboratory of bioenergetics at the Institute of Physiology CAS. He is an experienced biochemist who has devoted most of his professional career to the study of mitochondrial physiology. His main areas of interest are mitochondrial ATP synthase and mitochondrial energy converting enzymes in general, mitochondrial glycerol-3-phosphate dehydrogenase and its role in the production of reactive oxygen species, and the regulation of the mitochondrial oxidative phosphorylation apparatus. His postdoctoral work at the University of Liverpool focused on the regulation of energy metabolism at the organismal level by cytokines and adipokines. He has been the principal investigator of several grants from the Czech Science Foundation and the Czech Medical Research Council.

IPHYS contact person: Tomáš Mráček,