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Selected Publication:
Koshenov, Z.
Calcium regulation of mitochondrial bioenergetics in health and disease
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2022. pp. 90
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- Authors Med Uni Graz:
- Advisor:
- Graier Wolfgang
- Malli Roland
- Schindl Rainer
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- Abstract:
- Ca2+ is a versatile regulator of many cellular processes, including cellular and mitochondrial energy metabolism. To achieve precise control of metabolic processes, Ca2+ signalling events occur at specific locations and for certain duration. Main focus of the current dissertation is on differential spatial and temporal Ca2+ regulation of mitochondrial bioenergetics. Two main sites important for Ca2+ regulation of mitochondrial energy metabolism are mitochondrial matrix and mitochondrial intermembrane space (IMS). Matrix Ca2+ regulation of mitochondrial bioenergetics occurs through Ca2+ sensitive dehydrogenases of citric acid cycle. Main control spots for activation of matrix dehydrogenases are endoplasmic reticulum (ER)-mitochondria contact cites, or mitochondria associated ER membranes (MAMs), where the Ca2+ transfer from ER to mitochondria occurs. Ca2+ uptake into the matrix occurs through mitochondrial Ca2+ uniporter, and is regulated by a complex mechanism involving several proteins, which form MCU complex (MCUC). Composition of MCUC is altered under different pathological states and during aging. In the former case, as well as in certain cancers, mitochondrial uncoupling protein 2 (UCP2) was shown to play a major role in the regulation of matrix Ca2+ uptake through MCU. The first publication of the cumulative dissertation reviews the involvement of UCP2 in mitochondrial Ca2+ uptake in health and disease. The second regulatory site of mitochondrial bioenergetics is the IMS, which hosts Ca2+ sensitive NADH shuttles, malate-aspartate shuttle (MAS) and glycerol-phosphate shuttle. Since MAS forms the main shuttle in mammalian cells, it was the focus of the second publication. Ca2+ ions activate MAS at lower concentrations than matrix dehydrogenases, in addition to the absence of Ca2+ uptake threshold into the IMS, thus MAS is crucial for basal mitochondrial bioenergetics. As a result of high sensitivity of the NADH shuttle, it can respond to slight alterations in subcellular Ca2+ levels by rewiring cellular and mitochondrial bioenergetics. It provides a fast and reliable way to pre-emptively respond to cellular stress. The final publication of the cumulative dissertation is on Ca2+ mediated regulation of mitochondrial bioenergetics during early ER stress that is orchestrated by sigma-1 receptor (S1R). In this work, we have demonstrated that S1R directs the ER Ca2+ leak generated during early phases of ER stress towards mitochondria, which boosts mitochondrial energy production. S1R also plays a role in timely diversion of the leak away from mitochondria as the ER stress progresses, preventing mitochondrial Ca2+ overload. Thus, current dissertation adds new insights in spatial and time-resolved Ca2+ regulation of mitochondrial energy metabolism in health and disease, identifies new pathways, and open new venues for future research.