Artikel
Mitochondrial pathology in desminopathies: lessons from man and mice
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Autoren
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Rolf Schröder
- Institute of Neuropathology, Erlangen, Germany
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Lilli Winter
- Institute of Neuropathology, Erlangen, Germany
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Ilka Wittig
- Functional Proteomics, SFB815 Core Unit, Medical School, Frankfurt, Germany
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Viktoriya Peeva
- University Hospital Bonn, Life and Brain Center, Bonn, Germany
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Frederic Chevessier
- Institute of Neuropathology, Erlangen, Germany
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Rudolf Kley
- University Hospital Bergmannsheil, Dept. of Neurology, Bochum, Germany
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Katrin Marcus
- Ruhr University Bochum, Medizinisches Proteom-Center, Bochum, Germany
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Cornelia Kornblum
- University Hospital Bonn, Dept. of Neurology, Bonn, Germany
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Wolfram Kunz
- University Hospital Bonn, Life and Brain Center, Bonn, Germany
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Christoph Clemen
- Center for Biochemistry, Institute of Biochemistry 1, Köln, Germany
| Veröffentlicht: | 14. September 2016 |
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Gliederung
Text
Desminopathies are a group of familial and sporadic myopathies and cardiomyopathies that are caused by mutations in the human desmin gene on chromosome 2q35. They belong to the expanding group of protein aggregate myopathies and are currently classified in the subgroup of myofibrillar myopathies (MFMs). Several previous studies on muscle biopsy specimens from human desminopathies and other forms of MFMs reported on mitochondrial pathology.
In the present study, we investigated the relationship between mutant desmin and mitochondrial pathology by comprehensive and multi-level analyses in human and murine desminopathies. We demonstrate that the expression of mutant desmin leads to changes in the content, subcellular distribution, and morphology of mitochondria. Moreover, our proteomic and biochemical analyses provide strong evidence for a down-regulation of nuclear and mitochondrial DNA encoded respiratory chain and oxidative phosphorylation proteins, changes in mitochondrial enzyme activities, and defects in OXPHOS complex and supercomplex formation. Finally, our genetic analyses revealed reduced mtDNA copy numbers and increased large-scale mtDNA deletions. The overall data strongly imply that the mitochondrial pathology is an early key event in the pre-clinical disease stages of desminopathies.
