Impaired Mitochondrial Morphology and Functionality in <i>Lonp1</i><sup>wt/−</sup> Mice
LONP1 is a nuclear-encoded mitochondrial protease crucial for organelle homeostasis; mutations of <i>LONP1</i> have been associated with Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies (CODAS) syndrome. To clarify the role of LONP1 in vivo, we generated a mouse model in which...
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MDPI AG
2020-06-01
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| Series: | Journal of Clinical Medicine |
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| Online Access: | https://www.mdpi.com/2077-0383/9/6/1783 |
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| author | Anna De Gaetano Lara Gibellini Elena Bianchini Rebecca Borella Sara De Biasi Milena Nasi Federica Boraldi Andrea Cossarizza Marcello Pinti |
| author_facet | Anna De Gaetano Lara Gibellini Elena Bianchini Rebecca Borella Sara De Biasi Milena Nasi Federica Boraldi Andrea Cossarizza Marcello Pinti |
| author_sort | Anna De Gaetano |
| collection | DOAJ |
| description | LONP1 is a nuclear-encoded mitochondrial protease crucial for organelle homeostasis; mutations of <i>LONP1</i> have been associated with Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies (CODAS) syndrome. To clarify the role of LONP1 in vivo, we generated a mouse model in which <i>Lonp1</i> was ablated. The homozygous <i>Lonp<sup>−/−</sup></i> mouse was not vital, while the heterozygous <i>Lonp1<sup>wt/−</sup></i> showed similar growth rate, weight, length, life-span and histologic features as wild type. Conversely, ultrastructural analysis of heterozygous enterocytes evidenced profound morphological alterations of mitochondria, which appeared increased in number, swollen and larger, with a lower complexity. Embryonic fibroblasts (MEFs) from <i>Lonp1<sup>wt/−</sup></i> mice showed a reduced expression of <i>Lonp1</i> and <i>Tfam</i>, whose expression is regulated by LONP1. Mitochondrial DNA was also reduced, and mitochondria were swollen and larger, albeit at a lesser extent than enterocytes, with a perinuclear distribution. From the functional point of view, mitochondria from heterozygous MEF showed a lower oxygen consumption rate in basal conditions, either in the presence of glucose or galactose, and a reduced expression of mitochondrial complexes than wild type. In conclusion, the presence of one functional copy of the <i>Lonp1</i> gene leads to impairment of mitochondrial ultrastructure and functions in vivo. |
| first_indexed | 2024-03-10T19:18:01Z |
| format | Article |
| id | doaj.art-8544e80addf34b57a83d5c73febb5822 |
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| issn | 2077-0383 |
| language | English |
| last_indexed | 2024-03-10T19:18:01Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
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| series | Journal of Clinical Medicine |
| spelling | doaj.art-8544e80addf34b57a83d5c73febb58222023-11-20T03:12:20ZengMDPI AGJournal of Clinical Medicine2077-03832020-06-0196178310.3390/jcm9061783Impaired Mitochondrial Morphology and Functionality in <i>Lonp1</i><sup>wt/−</sup> MiceAnna De Gaetano0Lara Gibellini1Elena Bianchini2Rebecca Borella3Sara De Biasi4Milena Nasi5Federica Boraldi6Andrea Cossarizza7Marcello Pinti8Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, ItalyDepartment of Medical and Surgical Sciences of Children and Adults, University of Modena and Reggio Emilia, 41125 Modena, ItalyDepartment of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, 41125 Modena, ItalyDepartment of Medical and Surgical Sciences of Children and Adults, University of Modena and Reggio Emilia, 41125 Modena, ItalyDepartment of Medical and Surgical Sciences of Children and Adults, University of Modena and Reggio Emilia, 41125 Modena, ItalyDepartment of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, 41125 Modena, ItalyDepartment of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, ItalyDepartment of Medical and Surgical Sciences of Children and Adults, University of Modena and Reggio Emilia, 41125 Modena, ItalyDepartment of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, ItalyLONP1 is a nuclear-encoded mitochondrial protease crucial for organelle homeostasis; mutations of <i>LONP1</i> have been associated with Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies (CODAS) syndrome. To clarify the role of LONP1 in vivo, we generated a mouse model in which <i>Lonp1</i> was ablated. The homozygous <i>Lonp<sup>−/−</sup></i> mouse was not vital, while the heterozygous <i>Lonp1<sup>wt/−</sup></i> showed similar growth rate, weight, length, life-span and histologic features as wild type. Conversely, ultrastructural analysis of heterozygous enterocytes evidenced profound morphological alterations of mitochondria, which appeared increased in number, swollen and larger, with a lower complexity. Embryonic fibroblasts (MEFs) from <i>Lonp1<sup>wt/−</sup></i> mice showed a reduced expression of <i>Lonp1</i> and <i>Tfam</i>, whose expression is regulated by LONP1. Mitochondrial DNA was also reduced, and mitochondria were swollen and larger, albeit at a lesser extent than enterocytes, with a perinuclear distribution. From the functional point of view, mitochondria from heterozygous MEF showed a lower oxygen consumption rate in basal conditions, either in the presence of glucose or galactose, and a reduced expression of mitochondrial complexes than wild type. In conclusion, the presence of one functional copy of the <i>Lonp1</i> gene leads to impairment of mitochondrial ultrastructure and functions in vivo.https://www.mdpi.com/2077-0383/9/6/1783Lon proteaseCODASmitochondriamouse modelenterocytesmouse embryonic fibroblasts |
| spellingShingle | Anna De Gaetano Lara Gibellini Elena Bianchini Rebecca Borella Sara De Biasi Milena Nasi Federica Boraldi Andrea Cossarizza Marcello Pinti Impaired Mitochondrial Morphology and Functionality in <i>Lonp1</i><sup>wt/−</sup> Mice Journal of Clinical Medicine Lon protease CODAS mitochondria mouse model enterocytes mouse embryonic fibroblasts |
| title | Impaired Mitochondrial Morphology and Functionality in <i>Lonp1</i><sup>wt/−</sup> Mice |
| title_full | Impaired Mitochondrial Morphology and Functionality in <i>Lonp1</i><sup>wt/−</sup> Mice |
| title_fullStr | Impaired Mitochondrial Morphology and Functionality in <i>Lonp1</i><sup>wt/−</sup> Mice |
| title_full_unstemmed | Impaired Mitochondrial Morphology and Functionality in <i>Lonp1</i><sup>wt/−</sup> Mice |
| title_short | Impaired Mitochondrial Morphology and Functionality in <i>Lonp1</i><sup>wt/−</sup> Mice |
| title_sort | impaired mitochondrial morphology and functionality in i lonp1 i sup wt sup mice |
| topic | Lon protease CODAS mitochondria mouse model enterocytes mouse embryonic fibroblasts |
| url | https://www.mdpi.com/2077-0383/9/6/1783 |
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