Comprehensive Genetic Characterization of Mitochondrial Ca2+ Uniporter Components Reveals Their Different Physiological Requirements In Vivo
Summary: Mitochondrial Ca2+ uptake is an important mediator of metabolism and cell death. Identification of components of the highly conserved mitochondrial Ca2+ uniporter has opened it up to genetic analysis in model organisms. Here, we report a comprehensive genetic characterization of all known u...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-04-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112471930498X |
| _version_ | 1818846829196869632 |
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| author | Roberta Tufi Thomas P. Gleeson Sophia von Stockum Victoria L. Hewitt Juliette J. Lee Ana Terriente-Felix Alvaro Sanchez-Martinez Elena Ziviani Alexander J. Whitworth |
| author_facet | Roberta Tufi Thomas P. Gleeson Sophia von Stockum Victoria L. Hewitt Juliette J. Lee Ana Terriente-Felix Alvaro Sanchez-Martinez Elena Ziviani Alexander J. Whitworth |
| author_sort | Roberta Tufi |
| collection | DOAJ |
| description | Summary: Mitochondrial Ca2+ uptake is an important mediator of metabolism and cell death. Identification of components of the highly conserved mitochondrial Ca2+ uniporter has opened it up to genetic analysis in model organisms. Here, we report a comprehensive genetic characterization of all known uniporter components conserved in Drosophila. While loss of pore-forming MCU or EMRE abolishes fast mitochondrial Ca2+ uptake, this results in only mild phenotypes when young, despite shortened lifespans. In contrast, loss of the MICU1 gatekeeper is developmentally lethal, consistent with unregulated Ca2+ uptake. Mutants for the neuronally restricted regulator MICU3 are viable with mild neurological impairment. Genetic interaction analyses reveal that MICU1 and MICU3 are not functionally interchangeable. More surprisingly, loss of MCU or EMRE does not suppress MICU1 mutant lethality, suggesting that this results from uniporter-independent functions. Our data reveal the interplay among components of the mitochondrial Ca2+ uniporter and shed light on their physiological requirements in vivo. : Tufi et al. generate a genetic toolkit for all conserved components of the Drosophila mitochondrial calcium uniporter. Under basal conditions, MCU and EMRE loss is tolerated and MICU3 mutants are mildly impaired. MICU1 mutants are lethal, but this is not suppressed by MCU or EMRE loss, suggesting an unidentified uniporter-independent role. Keywords: mitochondria, calcium, MCU, MICU1, EMRE, MICU3, Drosophila, genetics, genetic interaction |
| first_indexed | 2024-12-19T05:51:46Z |
| format | Article |
| id | doaj.art-c1bb1441093a4312a88764ae33233a75 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-19T05:51:46Z |
| publishDate | 2019-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-c1bb1441093a4312a88764ae33233a752022-12-21T20:33:35ZengElsevierCell Reports2211-12472019-04-0127515411550.e5Comprehensive Genetic Characterization of Mitochondrial Ca2+ Uniporter Components Reveals Their Different Physiological Requirements In VivoRoberta Tufi0Thomas P. Gleeson1Sophia von Stockum2Victoria L. Hewitt3Juliette J. Lee4Ana Terriente-Felix5Alvaro Sanchez-Martinez6Elena Ziviani7Alexander J. Whitworth8MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UKMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UKDepartment of Biology, University of Padova, Padova, Italy; Fondazione Ospedale San Camillo, IRCCS, Lido di Venezia, Venezia, ItalyMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UKMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UKMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UKMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UKDepartment of Biology, University of Padova, Padova, Italy; Fondazione Ospedale San Camillo, IRCCS, Lido di Venezia, Venezia, ItalyMRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK; Corresponding authorSummary: Mitochondrial Ca2+ uptake is an important mediator of metabolism and cell death. Identification of components of the highly conserved mitochondrial Ca2+ uniporter has opened it up to genetic analysis in model organisms. Here, we report a comprehensive genetic characterization of all known uniporter components conserved in Drosophila. While loss of pore-forming MCU or EMRE abolishes fast mitochondrial Ca2+ uptake, this results in only mild phenotypes when young, despite shortened lifespans. In contrast, loss of the MICU1 gatekeeper is developmentally lethal, consistent with unregulated Ca2+ uptake. Mutants for the neuronally restricted regulator MICU3 are viable with mild neurological impairment. Genetic interaction analyses reveal that MICU1 and MICU3 are not functionally interchangeable. More surprisingly, loss of MCU or EMRE does not suppress MICU1 mutant lethality, suggesting that this results from uniporter-independent functions. Our data reveal the interplay among components of the mitochondrial Ca2+ uniporter and shed light on their physiological requirements in vivo. : Tufi et al. generate a genetic toolkit for all conserved components of the Drosophila mitochondrial calcium uniporter. Under basal conditions, MCU and EMRE loss is tolerated and MICU3 mutants are mildly impaired. MICU1 mutants are lethal, but this is not suppressed by MCU or EMRE loss, suggesting an unidentified uniporter-independent role. Keywords: mitochondria, calcium, MCU, MICU1, EMRE, MICU3, Drosophila, genetics, genetic interactionhttp://www.sciencedirect.com/science/article/pii/S221112471930498X |
| spellingShingle | Roberta Tufi Thomas P. Gleeson Sophia von Stockum Victoria L. Hewitt Juliette J. Lee Ana Terriente-Felix Alvaro Sanchez-Martinez Elena Ziviani Alexander J. Whitworth Comprehensive Genetic Characterization of Mitochondrial Ca2+ Uniporter Components Reveals Their Different Physiological Requirements In Vivo Cell Reports |
| title | Comprehensive Genetic Characterization of Mitochondrial Ca2+ Uniporter Components Reveals Their Different Physiological Requirements In Vivo |
| title_full | Comprehensive Genetic Characterization of Mitochondrial Ca2+ Uniporter Components Reveals Their Different Physiological Requirements In Vivo |
| title_fullStr | Comprehensive Genetic Characterization of Mitochondrial Ca2+ Uniporter Components Reveals Their Different Physiological Requirements In Vivo |
| title_full_unstemmed | Comprehensive Genetic Characterization of Mitochondrial Ca2+ Uniporter Components Reveals Their Different Physiological Requirements In Vivo |
| title_short | Comprehensive Genetic Characterization of Mitochondrial Ca2+ Uniporter Components Reveals Their Different Physiological Requirements In Vivo |
| title_sort | comprehensive genetic characterization of mitochondrial ca2 uniporter components reveals their different physiological requirements in vivo |
| url | http://www.sciencedirect.com/science/article/pii/S221112471930498X |
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