Kiraly, S.; Martello, A.; Platt, F. M.; Eden, E. R.

Niemann-Pick disease type-C (NPC) is a progressive neurodegenerative disease caused by loss-of-function mutations in NPC1 or NPC2. In NPC patient cells lacking functional NPC proteins, lipids accumulate in lysosomes causing severe lysosomal storage disease. Surprisingly, lipid accumulation caused by defects in the lysosomal membrane protein NPC1 is strongly associated with mitochondrial dysfunction. The mechanism of this coupled dysfunction is not fully understood, but a recently approved NPC therapeutic, N-Acetyl-l-Leucine (NALL), reverses both lysosomal and mitochondrial phenotypes in NPC patient cells. Our data indicate that direct inter-organelle communication through lysosome membrane contact sites with mitochondria contribute to the coupled organelle dysfunction in NPC. We find that mitochondria:lysosome contact sites are expanded in NPC, dependent on accumulation of lysosomal cholesterol and that NALL rescues the aberrant contact sites. We further identify a direct correlation between mitochondria:lysosome contact site expansion and mitochondrial dysfunction and propose that normalisation of contacts sites contributes to the coupled restoration of lysosome and mitochondrial function by NALL. We further find that NALL-mediated normalisation of lysosomal contact sites also correlates with restoration of autophagic flux and lysosome repair in NPC patient cells.