Impaired parkin-mediated mitochondrial targeting to autophagosomes differentially contributes to tissue pathology in lysosomal storage diseases
| Autor: | Raquel de Pablo-Latorre, Elena V. Polishhuck, Edoardo Nusco, Assunta Saide, Alessandro Fraldi, Andrea Ballabio |
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| Přispěvatelé: | de Pablo Latorre, R, Saide, A, Polishhuck, Ev, Nusco, E, Fraldi, Alessandro, Ballabio, Andrea |
| Rok vydání: | 2012 |
| Předmět: |
Multiple Sulfatase Deficiency Disease
Ubiquitin-Protein Ligases Apoptosis Mitochondria Liver Mitochondrion Biology Parkin 03 medical and health sciences Mice 0302 clinical medicine Multiple sulfatase deficiency Phagosomes Mitophagy Genetics medicine Autophagy Animals Molecular Biology Genetics (clinical) 030304 developmental biology 0303 health sciences Neurodegeneration Ubiquitination Brain Cytochromes c General Medicine Articles medicine.disease 3. Good health Cell biology Mitochondria Disease Models Animal mitochondrial fusion Liver 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics Human Molecular Genetics; Vol 21 |
| ISSN: | 1460-2083 |
| Popis: | Dysfunctional mitochondria are a well-known disease hallmark. The accumulation of aberrant mitochondria can alter cell homeostasis, thus resulting in tissue degeneration. Lysosomal storage disorders (LSDs) are a group of inherited diseases characterized by the buildup of undegraded material inside the lysosomes that leads to autophagic-lysosomal dysfunction. In LSDs, autophagic stress has been associated to mitochondrial accumulation and dysfunction. However, the mechanisms underlying mitochondrial aberrations and how these are involved in tissue pathogenesis remain largely unexplored. In normal conditions, mitochondrial clearance occurs by mitophagy, a selective form of autophagy, which relies on a parkin-mediated mitochondrial priming and subsequent sequestration by autophagosomes. Here, we performed a detailed analysis of key steps of mitophagy in a mouse model of multiple sulfatase deficiency (MSD), a severe type of LSD characterized by both neurological and systemic involvement. We demonstrated that in MSD liver reduced parkin levels resulted in inefficient mitochondrial priming, thus contributing to the accumulation of giant mitochondria that are located outside autophagic vesicles ultimately leading to cytochrome c release and apoptotic cell death. Morphological and functional changes were also observed in mitochondria from MSD brain but these were not directly associated with neuronal cell loss, suggesting a secondary contribution of mitochondria to neurodegeneration. Together, these data shed new light on the mechanisms underlying mitochondrial dysfunction in LSDs and on their tissue-specific differential contribution to the pathogenesis of this group of metabolic disorders. |
| Databáze: | OpenAIRE |
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