Impact of Organelle Transport Deficits on Mitophagy and Autophagy in Niemann-Pick Disease Type C.

Maik Liedtke,Moritz J Frech,Andreas Hermann,Christin Völkner

doi:10.3390/cells11030507

Abstract

Defective mitochondria are pathophysiological features of a number of neurodegenerative diseases. Here, we investigated mitochondrial dysfunction in the context of the rare lysosomal storage diseases Niemann–Pick disease type C1 and type C2 (NP-C1 and NP-C2). Mutations in either the NPC1 or NPC2 gene lead to cholesterol accumulation in late endosomes and lysosomes, resulting in impaired cholesterol homeostasis. The extent to which this may lead to mitochondrial dysfunction has been poorly studied so far. Therefore, we investigated the morphology, function, and transport of mitochondria, as well as their degradation via mitophagy, in a disease-associated human neural cell model of NP-C. By performing live cell imaging, we observed markedly reduced mitochondrial transport, although morphology and function were not appreciably altered. However, we observed a defective mitophagy induction shown by a reduced capability to elevate parkin expression and engulf mitochondria in autophagosomes after treatment with carbonyl cyanide 3-chlorophenylhydrazone (CCCP). This was accompanied by defects in autophagy induction, exhibited by a hampered p62 expression and progression, shown by increased LC3BII levels and a defective fusion of autophagosomes and lysosomes. The latter might have been additionally influenced by the observed reduced lysosomal transport. Hence, we hypothesized that a reduced recycling of mitochondria contributes to the pathophysiology of NP-C.

Highlights

Publisher’s Note: MDPI stays neutralDisturbances of mitochondrial morphology, movement, and function are pathophysiological features of a number of neurodegenerative diseases
As a reduced size might have had an impact on the functionality, we evaluated the number of organelles (Figure 2a,b), their stress levels (Figure 2c,d), and their membrane potentials (Figure 2e,f)
As mitophagy is initiated by parkin, an E3 ubiquitin ligase that is recruited to mitochondria and binds to the mitochondrial rho GTPase 1 and/or 2 (Miro1 and 2) for ubiquitination and targets them for degradation [11,28], we evaluated the expression of this ligase with and without mitochondrial damage

Summary

Introduction

Disturbances of mitochondrial morphology, movement, and function are pathophysiological features of a number of neurodegenerative diseases. We investigated mitochondrial dysfunction in the context of the rare lysosomal storage diseases. NP-C is caused by mutations in the NPC1 (95% of cases) or NPC2 (5% of cases) gene, coding for the NPC1 and NPC2 proteins, which cooperate to transport cholesterol out of late endosomes and lysosomes, and maintain the intracellular cholesterol homeostasis [1,2]. Mutations in one of the two genes result in a pathophysiological accumulation of cholesterol and sphingolipids in these organelles [3]. An increase in cholesterol in the mitochondrial membranes was described in a murine NP-C1 model, which was accompanied by with regard to jurisdictional claims in published maps and institutional affiliations

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Conclusion