Characterization of a Cell Death Mechanism in a Mouse Model of Multiple Sulfatase Deficiency: Role of Mitochondrial Autophagy

De Pablo Latorre, Raquel (2011). Characterization of a Cell Death Mechanism in a Mouse Model of Multiple Sulfatase Deficiency: Role of Mitochondrial Autophagy. PhD thesis The Open University.



Mitochondria are organelles recognized as central players in cell death. Dysfunctional mitochondria are a well-known hallmark of disease since the accumulation of aberrant mitochondria can alter cell homeostasis thus resulting in tissue degeneration. Lysosomal storage disorders (LSDs) are a group of genetic diseases characterized by the accumulation of un-degraded material inside lysosomes that leads to autophagic-lysosomal function failure. In LSDs, mitochondrial aberrations have been associated to autophagic stress. However, the mechanisms by which autophagic deregulation determines mitochondrial dysfunction and how such alterations are involved in tissue pathogenesis remain largely unexplored. Normally, mitochondrial clearance occurs by a selective form of autophagy, known as mitophagy, which relies on a parkin- mediated mitochondrial priming and subsequent engulfment by autophagosomes. Here, we have performed a comprehensive analysis of mitophagy in a mouse model of Multiple sulfatase deficiency (MSD), an LSD characterized by both severe neurological and systemic involvement. We demonstrated that, in MSD liver, reduced parkin results in an inefficient mitochondrial turnover thus determining the accumulation of effete organelles outside autophagic vesicles. As consequence, dysfunctional mitochondria release cytochrome c into the cytosol ultimately leading to apoptotic cell death. Otherwise, in MSD brain, we observed minor morphological and functional changes that could not be directly associated to specific defects in mitochondrial priming machinery. Together these data provide new evidences on the mechanisms underlying mitochondrial dysfunction in LSDs and indicate that mitochondrial alterations differently contribute to tissue pathogenesis in a mouse model of LSD.

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