A disease-associated Aifm1 variant induces severe myopathy in knockin mice
Objective: Mutations in the AIFM1 gene have been identified in recessive X-linked mitochondrial diseases. Functional and molecular consequences of these pathogenic AIFM1 mutations have been poorly studied in vivo. Methods/results: Here we provide evidence that the disease-associated apoptosis-induci...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-07-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877818302485 |
| _version_ | 1819022224132145152 |
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| author | Lena Wischhof Anna Gioran Dagmar Sonntag-Bensch Antonia Piazzesi Miriam Stork Pierluigi Nicotera Daniele Bano |
| author_facet | Lena Wischhof Anna Gioran Dagmar Sonntag-Bensch Antonia Piazzesi Miriam Stork Pierluigi Nicotera Daniele Bano |
| author_sort | Lena Wischhof |
| collection | DOAJ |
| description | Objective: Mutations in the AIFM1 gene have been identified in recessive X-linked mitochondrial diseases. Functional and molecular consequences of these pathogenic AIFM1 mutations have been poorly studied in vivo. Methods/results: Here we provide evidence that the disease-associated apoptosis-inducing factor (AIF) deletion arginine 201 (R200 in rodents) causes pathology in knockin mice. Within a few months, posttranslational loss of the mutant AIF protein induces severe myopathy associated with a lower number of cytochrome c oxidase-positive muscle fibers. At a later stage, Aifm1 (R200 del) knockin mice manifest peripheral neuropathy, but they do not show neurodegenerative processes in the cerebellum, as observed in age-matched hypomorphic Harlequin (Hq) mutant mice. Quantitative proteomic and biochemical data highlight common molecular signatures of mitochondrial diseases, including aberrant folate-driven one-carbon metabolism and sustained Akt/mTOR signaling. Conclusion: Our findings indicate metabolic defects and distinct tissue-specific vulnerability due to a disease-causing AIFM1 mutation, with many pathological hallmarks that resemble those seen in patients. Keywords: Akt/mTOR signaling, Apoptosis-inducing factor (AIF), 1C metabolism, Mitochondria, Mitochondrial diseases, Oxidative phosphorylation |
| first_indexed | 2024-12-21T04:19:36Z |
| format | Article |
| id | doaj.art-1562a901260a4e399a927d1c411efcdb |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-21T04:19:36Z |
| publishDate | 2018-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-1562a901260a4e399a927d1c411efcdb2022-12-21T19:16:13ZengElsevierMolecular Metabolism2212-87782018-07-01131023A disease-associated Aifm1 variant induces severe myopathy in knockin miceLena Wischhof0Anna Gioran1Dagmar Sonntag-Bensch2Antonia Piazzesi3Miriam Stork4Pierluigi Nicotera5Daniele Bano6German Center for Neurodegenerative Diseases (DZNE), Bonn, GermanyGerman Center for Neurodegenerative Diseases (DZNE), Bonn, GermanyGerman Center for Neurodegenerative Diseases (DZNE), Bonn, GermanyGerman Center for Neurodegenerative Diseases (DZNE), Bonn, GermanyGerman Center for Neurodegenerative Diseases (DZNE), Bonn, GermanyGerman Center for Neurodegenerative Diseases (DZNE), Bonn, GermanyCorresponding author. Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Sigmund-Freud-Str. 27, 53127 Bonn, Germany. Tel.: +49 228 43302 510, Fax: +49 228 43302 689.; German Center for Neurodegenerative Diseases (DZNE), Bonn, GermanyObjective: Mutations in the AIFM1 gene have been identified in recessive X-linked mitochondrial diseases. Functional and molecular consequences of these pathogenic AIFM1 mutations have been poorly studied in vivo. Methods/results: Here we provide evidence that the disease-associated apoptosis-inducing factor (AIF) deletion arginine 201 (R200 in rodents) causes pathology in knockin mice. Within a few months, posttranslational loss of the mutant AIF protein induces severe myopathy associated with a lower number of cytochrome c oxidase-positive muscle fibers. At a later stage, Aifm1 (R200 del) knockin mice manifest peripheral neuropathy, but they do not show neurodegenerative processes in the cerebellum, as observed in age-matched hypomorphic Harlequin (Hq) mutant mice. Quantitative proteomic and biochemical data highlight common molecular signatures of mitochondrial diseases, including aberrant folate-driven one-carbon metabolism and sustained Akt/mTOR signaling. Conclusion: Our findings indicate metabolic defects and distinct tissue-specific vulnerability due to a disease-causing AIFM1 mutation, with many pathological hallmarks that resemble those seen in patients. Keywords: Akt/mTOR signaling, Apoptosis-inducing factor (AIF), 1C metabolism, Mitochondria, Mitochondrial diseases, Oxidative phosphorylationhttp://www.sciencedirect.com/science/article/pii/S2212877818302485 |
| spellingShingle | Lena Wischhof Anna Gioran Dagmar Sonntag-Bensch Antonia Piazzesi Miriam Stork Pierluigi Nicotera Daniele Bano A disease-associated Aifm1 variant induces severe myopathy in knockin mice Molecular Metabolism |
| title | A disease-associated Aifm1 variant induces severe myopathy in knockin mice |
| title_full | A disease-associated Aifm1 variant induces severe myopathy in knockin mice |
| title_fullStr | A disease-associated Aifm1 variant induces severe myopathy in knockin mice |
| title_full_unstemmed | A disease-associated Aifm1 variant induces severe myopathy in knockin mice |
| title_short | A disease-associated Aifm1 variant induces severe myopathy in knockin mice |
| title_sort | disease associated aifm1 variant induces severe myopathy in knockin mice |
| url | http://www.sciencedirect.com/science/article/pii/S2212877818302485 |
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