Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Jean-Quartier, C.
New and old entities in mitochondrial Ca2+ uptake
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medical University of Graz; 2014. pp. 161
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- Autor*innen der Med Uni Graz:
- Jean-Quartier Claire
- Betreuer*innen:
- Graier Wolfgang
- Malli Roland
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- Abstract:
- The process of mitochondrial Ca2+ sequestration across the inner mitochondrial membrane plays a central role in cell signal transduction and is pivotal for important cell and organelle function. The aim of this study is to identify proteins involved in this process and to assign their function. Very recently, the mitochondrial calcium uniport protein (MCU), mitochondrial Ca2+ uptake 1 and 2 (MICU1/2), mitochondrial Ca2+ uptake regulator (MCUR), essential MCU regulator (EMRE), uncoupling proteins 2 and 3 (UCP2/3) and leucine zipper EF hand-containing transmembrane protein (LETM1) have been described as contributors to the mitochondrial Ca2+ uptake machinery. Additionally, alternative proteins involved in mitochondrial Ca2+ uptake have been described including solute carrier protein SLC25A23, mitochondrial ryanodine receptors (RYR) and transient receptor canonical potential cation channels TRPC3, not exclusively targeted to mitochondria. We have confirmed previous observations that the MCU/MICU1 complex holds a primary role in mitochondrial Ca2+ accumulation and corroborated previous work on an engagement of UCP2/3 and Letm1 in mitochondrial Ca2+ sequestration. Notably, we have demonstrated that depending on SERCA activity, different mitochondrial Ca2+ uptake routes with molecularly distinct contributors are engaged upon IP3 mediated ER Ca2+ release. By applying electrophysiological measurements of the inner mitochondrial membrane at least three biophysically distinct Ca2+ currents could be verified, whose two essentially depend on the presence of MCU and UCP2/3, respectively. Finally, functional data highlight interdependency between these putative mitochondrial Ca2+ carriers and native proteomics disclose various complex formations of the individual proteins MCU, MICU1, UCP2/3 or Letm1. Our findings suggest multiple Ca2+ entry pathways based on a variable set of interacting proteins that result in the assembly of Ca2+ pores with distinct biophysical characteristics. In addition, using the example of MICOS, we demonstrate the impact of mitochondrial structure handling proteins on mitochondrial Ca2+ sequestration. Still, precise understanding of the mechanisms of mitochondrial Ca2+ uptake, molecular structure and function of mitochondrial Ca2+ channels is of particular importance for future therapeutic modulation of mitochondrial function a phenomenon linked to many severe human diseases.