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http://doi.org/10.25358/openscience-6798Full metadata record
| DC Field | Value | Language |
|---|---|---|
| dc.contributor.author | Dietsche, Felicia | - |
| dc.date.accessioned | 2022-03-08T12:35:38Z | - |
| dc.date.available | 2022-03-08T12:35:38Z | - |
| dc.date.issued | 2022 | - |
| dc.identifier.uri | https://openscience.ub.uni-mainz.de/handle/20.500.12030/6809 | - |
| dc.description.abstract | Mitochondria are dynamic organelles with a central role in many vital processes. Besides ATP generation and other functions, they are crucial for cellular Ca2+ buffering. In close cooperation with the endoplasmic reticulum, mitochondria can shape cytosolic Ca2+ signals by taking in Ca2+. Free Ca2+ in the mitochondrial matrix enhances ATP production which links mitochondrial metabolism to the cellular energy demand. Only a decade ago, the mitochondrial Ca2+ uptake pore was identified as the Mitochondrial Calcium Uniporter (MCU). However, MCU knockout (KO) mice are viable and lack a drastic phenotype. This created doubts about the singularity of MCU. We propose the Transmembrane BAX Inhibitor Motif containing protein (TMBIM) 5 as a novel mitochondrial Ca2+ channel. TMBIM5 is ubiquitously expressed, localises to the inner mitochondrial membrane and shares conserved sequence homologies with TMBIM6 and the bacterial homologue BsYetJ. Both are pH-dependent Ca2+ channels. Loss of TMBIM5 leads to a disruption in the cristae structure. Using TMBIM5 KO cell lines (HAP1/HEK293), I demonstrated that it does not interact with the mitochondrial contact site and cristae organizing system. The KO impairs mitochondrial Ca2+ uptake and affects the expression of MCU and its regulator Mitochondrial Calcium Uptake 1. In addition, I detected changes in the abundance and processing of Optical Atrophy 1 (OPA1), a protein involved in cristae stabilisation. Its dysregulation may cause the observed abnormal cristae structure. To study the effect of TMBIM5 in vivo, we obtained a mouse line containing an amino acid exchange (D326R) in the putative pore domain. The analogue mutation induces a loss-of-function in TMBIM6. Similar to MCU KO, the mice did not show any gross phenotype. Yet, they were born at a reduced Mendelian rate and the mutated protein was downregulated in the adult animals. Screening for functional abnormalities revealed a striking cell-type dependence. The skeletal muscle is most severely affected by myopathy and dysregulation in mitochondrial Ca2+ uptake and buffering. My results indicate that TMBIM5 is involved in mitochondrial Ca2+ handling and presumably only indirectly affects mitochondrial cristae structure. The tissue-specificity in the mouse suggests that additional regulatory elements may exist that affect TMBIM5 function. | en_GB |
| dc.language.iso | eng | de |
| dc.rights | CC BY-ND | * |
| dc.rights.uri | https://creativecommons.org/licenses/by-nd/4.0/ | * |
| dc.subject.ddc | 500 Naturwissenschaften | de_DE |
| dc.subject.ddc | 500 Natural sciences and mathematics | en_GB |
| dc.subject.ddc | 570 Biowissenschaften | de_DE |
| dc.subject.ddc | 570 Life sciences | en_GB |
| dc.title | The effect of knockout and mutation of the Transmembrane BAX Inhibitor Motif containing Protein 5 (TMBIM5) on cellular and mitochondrial function in cells and mice | en_GB |
| dc.type | Dissertation | de |
| dc.identifier.urn | urn:nbn:de:hebis:77-openscience-c32a476e-dfcc-4d8c-ad71-64b6145a5d565 | - |
| dc.identifier.doi | http://doi.org/10.25358/openscience-6798 | - |
| jgu.type.dinitype | doctoralThesis | en_GB |
| jgu.type.version | Original work | de |
| jgu.type.resource | Text | de |
| jgu.date.accepted | 2022-01-31 | - |
| jgu.organisation.department | FB 10 Biologie | de |
| jgu.organisation.number | 7970 | - |
| jgu.organisation.name | Johannes Gutenberg-Universität Mainz | - |
| jgu.rights.accessrights | openAccess | - |
| jgu.organisation.place | Mainz | - |
| jgu.subject.ddccode | 500 | de |
| jgu.subject.ddccode | 570 | de |
| jgu.organisation.ror | https://ror.org/023b0x485 | |
| Appears in collections: | JGU-Publikationen | |
Files in This Item:
| File | Description | Size | Format | ||
|---|---|---|---|---|---|
 | the_effect_of_knockout_and_mu-20220302095917613.pdf | 5.04 MB | Adobe PDF | View/Open |