Medizinische Universität Graz - Research portal
Selected Publication:
Trenker, M.
Studying the physiological function of uncoupling protein 2 and 3 and their impact on mitochondrial Ca2+ homeostasis
[ Dissertation ] Medical University of Graz; 2007. pp.127.
- Authors Med Uni Graz:
- Trenker Michael
- Advisor:
- Graier Wolfgang
- Wascher Thomas
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- Abstract:
- Within cells Calcium (CA2+) serves as an ubiquitous second messenger that controls a diverse range of cellular processes, such as gene transcription, muscle contraction, cell proliferation and cell death. Furthermore, Ca2+ uptake into the mitochondria has been shown to be crucial for the regulation of the rate of oxidative phosphorylation, the modulation of spatiotemporal cytosolic Ca2+ signals, maintenance of store operated Ca2+ entry pathways, and apoptosis. While the phenomenon of mitochondrial Ca2+ sequestration, its characteristics and physiological consequences have been convincingly reported, the actual protein(s) that are involved in this process is/are still unknown. While the phenomenon of mitochondrial Ca2+ sequestration, its characteristics and physiological consequences have been convincingly reported, the actual protein(s) that are involved in this process is/are still unknown. The uncoupling proteins 2 and 3 (UCP2 and UCP3) are embedded in the inner mitochondrial membrane and belong to the super-family of mitochondrial ion transporters. Both proteins are homologues of the well characterized uncoupling protein 1 (UCP1), which is preferentially expressed in brown adipose tissue and accounts for thermogenesis by inducing a H+ leak that uncouples oxidative phosphorylation. In contrast, the function of UCP2 and UCP3 that have been identified in many tissues is still unclear and their involvement in uncoupling respiration and thermogenesis is still matter of debate. In the present study, the physiological function of uncoupling protein 2 and 3 and their participation in mitochondrail Ca2+ uniport was explored. Using several biochemical strategies such as protein overexpression, gene silencing via siRNAs and mutagenesis of UCP2 and UCP3, UCP2 and UCP3 are demonstrated to be elementary for mitochondria Ca2+ uniport in response to cellular stimulation under physiological conditions. Isolated liver mitochondria from UCP2-/- mice, which lacked a ruthenium red-sensitive Ca2+ uptake further support this concept. Our results reveal a novel molecular function of these UCP orthologs and may provide the molecular mechanism beyond the effects of UCP2 and UCP3 reported in the literature. Although it remains unclear whether of not UCP2 and UPC3 represent the channel proteins responsible for mitochondrial Ca2+ sequestration, the characterization of these two proteins as to be elementary contributors to mitochondrial Ca2+ uniport, provides unique possibilities for further elucidation of its mechanism and its physiological and pathological role.