| First Author | Wischhof L | Year | 2018 |
| Journal | Mol Metab | Volume | 13 |
| Pages | 10-23 | PubMed ID | 29780003 |
| Mgi Jnum | J:315749 | Mgi Id | MGI:6823063 |
| Doi | 10.1016/j.molmet.2018.05.002 | Citation | Wischhof L, et al. (2018) A disease-associated Aifm1 variant induces severe myopathy in knockin mice. Mol Metab 13:10-23 |
| abstractText | 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. |
