Metabolic Regulation Research Group

Our current focus

Metabolic regulation research groups’ main focus is understanding the role of hypoxia and hypothermia in the control of metabolism by using genetic models, biochemistry, molecular biology, measurement of O2 and CO2 in response to different nutrients and oxygen concentration, and state of the art metabolomics and tracing techniques.

Therapeutic hypothermia (32C) is regarded as one of the most promising future interventions for the treatment of acute ischemic stroke, however, uncertainty around why and how hypothermia provides protection is still a challenge. In a recent study our group has demonstrated for the first time that mild hypothermia (32C) activates Nuclear factor erythroid 2-related factor 2 (Nrf2), a major regulator of antioxidant gene transcription, and provides protection from oxidative stress presumably by orchestrating adaptive responses to redox stress. Currently, it is widely accepted that therapeutic effects of hypothermia are due to thermodynamic effects of metabolic depression. However, our results suggest that mild hypothermia extensively remodels gene expression and activates specific signaling pathways leading to increased stress tolerance during oxygen restriction.

Reductive stress is an understudied concept, which lies at the roots of oxidative stress. Numerous studies have indicated that ischemia reperfusion injury and electron transport chain diseases can lead to an overabundance of reducing equivalents (NADH, NADPH, succinate) facilitating oxidative stress and cellular injury.  We have recently developed a unique cellular respiration monitoring system to determine O2 and CO2 fluxes in intact cells in real time. It allows us to measure the production (by CAC, citric acid cycle) and utilization (by ETC, electron transport chain) of reducing power. The main aim of the project is to gain mechanistic insights on the accumulation of reducing equivalents in hypoxic conditions and release during reperfusion.

Ongoing projects

• Identification of cold inducible proteins that are coordinating the cellular response to hypothermia.
• VHL-deficiency leads to reductive stress in renal cells.
• We have recently established that anoxic incubation of intact cells lowers the activity of CAC to 15-20% of the baseline, but does not abolish it. Since ETC is not functional in anoxia and citrate to AcCoA conversion requires ATP, which is scarce in anoxia, there seems to be an overproduction of reducing equivalents in anoxia. Ongoing research seeks to elucidate the molecular and metabolic processes involved in anoxic CO2 production and reductive stress.

Grants

• Estonian Research Council: HIF1B as a Novel Hypothermia Response Factor with Therapeutic Benefits (Research Fellow Kattri-Liis Eskla, GMVBS24069PS, 01.01.2024−31.12.2028)

Current collaborations

Estonia:

• University of Tartu, Institute of Biomedicine and Translational Medicine, Department of Pathophysiology

International:

• Prof Daniel A. Tennant, University of Birmingham, Institute of Metabolism and Systems Research, Hypoxia and Metabolism Group, UK 

The most important publications

• Eskla KL, Vellama H, Tarve L, Eichelmann H, Jagomäe T, Porosk R, Oja V, Rämma H, Peet N, Laisk A, Volke V, Vasar E, Luuk H. Hypothermia Alleviates Reductive Stress, a Root Cause of Ischemia Reperfusion Injury. Int J Mol Sci. 2022 Sep 3;23(17):10108. doi: 10.3390/ijms231710108. PMID: 36077504; PMCID: PMC9456258.
• Westbrook RL, Bridges E, Roberts J, Escribano-Gonzalez C, Eales KL, Vettore LA, Waler PD, Vera-Siguenza E, Cuozzo F, Eskla KL, Vellama H, Shaaban A, Nixon C, Luuk H, Lavery GG, Hodson D, Harris A, Tennant DA.Proline Synthesis Through PYCR1 is Required to Support Cancer Cell Proliferation and Survival in Oxygen-Limiting Conditions. Cell Reports. 2021.
• Eskla KL, Porosk R, Reimets R, Visnapuu T, Vasar E, Hundahl CA, Luuk H. Hypothermia augments stress response in mammalian cells. Free Radic Biol Med. 2018 Jun;121:157-168. doi: 10.1016/j.freeradbiomed.2018.04.571. Epub 2018 Apr 25. PMID: 29704622.
• Ilmjärv S, Hundahl CA, Reimets R, Niitsoo M, Kolde R, Vilo J, Vasar E, Luuk H. Estimating differential expression from multiple indicators. Nucleic Acids Res. 2014 Apr;42(8):e72. doi: 10.1093/nar/gku158. Epub 2014 Feb 27. PMID: 24586062; PMCID: PMC4005682.