VPS13A, a closely associated mitochondrial protein, is required for efficient lysosomal degradation

Abstract

Members of the VPS13 family are associated with various human diseases. In particular, the loss of function of VPS13A leads to chorea-acanthocytosis (ChAc), a rare neurodegenerative disease without available curative treatments. Autophagy has been considered a promising therapeutic target because the absence of VPS13A causes a defective autophagy flux. However, the mechanistic details of this deficiency are unknown. Here, we identified Rab7A as an interactor of one of the VPS13 family members in Dictyostelium discoideum and showed that this interaction is conserved between the human homologs VPS13A and RAB7A in HeLa cells. As RAB7A is a key player in endosome trafficking, we addressed the possible function of VPS13A in endosome dynamics and lysosome degradation. Our results suggest that the decrease in autophagy observed in the absence of VPS13A may be the result of a more general defect in endocytic trafficking and lysosomal degradation. Unexpectedly, we found that VPS13A is closely localized to mitochondria, suggesting that the role of VPS13A in the endolysosomal pathway might be related to inter-organelle communication. We show that VPS13A localizes at the interface between mitochondria-endosomes and mitochondria-endoplasmic reticulum and that the presence of membrane contact sites is altered in the absence of VPS13A. Based on these findings, we propose that therapeutic strategies aimed at modulating the endolysosomal pathway could be beneficial in the treatment of ChAc.

Combined Dendritic and Axonal Deterioration Are Responsible for Motoneuronopathy in Patient-Derived Neuronal Cell Models of Chorea-Acanthocytosis

“…In order to shed light if this is due to an overproduction of lysosomal vesicles or due a deficit in downstream fusion of these compartments, further experiments need to be conducted. Even though we did not comprehensively investigate the underlying mechanism, both possibilities suggest an impairment of this pathway, as was described previously [25,32]. The altered transport features of these compartments can be a secondary effect due to mitochondrial failure to provide enough ATP to the cells or it can be indicative that the underlying rails-the microtubules-are defective.…”

“…Major advances in understanding the pathomechanism of ChAc and the function of chorein and its orthologues have been made recently [7][8][9][10]25]. Still, the main focus of the scientific community lies on the investigation of erythrocyte and medium spiny neuron (MSN) phenotypes as the primarily affected cell types.…”

Metabolic implications of organelle–mitochondria communication

“…Recently, cutting-edge microscopy studies have detected the establishment of physical contacts between lysosomes and mitochondria in healthy cells in the absence of damage stimulus [1,233]. Besides, the latest discoveries in the field point to RAB7 as a master coordinator of these contacts [6,7,[234][235][236] (Fig 6).…”

“…This interaction increases upon ª 2019 The Authors EMBO reports 20: e47928 | 2019 autophagy induction by starvation and has been proposed to be key for autophagosome-lysosome fusion [234]. A recent study indicates that lysosomal RAB7 immunoprecipitates and partially colocalizes with mitochondrial VPS13A in HeLa cells and that the absence of VPS13A causes impaired lysosomal degradation [236]. Moreover, a different study has identified a hydrophobic cavity in the structure of this protein and has proved its capacity to bind and transfer phospholipids between two membranes [238].…”

Staying in touch with the endocytic network: The importance of contacts for cholesterol transport

“…Hsu et al described reversible translocation of Rab5 from early endosomes to mitochondria at MCS under conditions of oxidative stress and active membrane‐bound Rab7 was found to promote mitochondria‐lysosome MCS that mark sites of mitochondrial fission . Moreover, the role of Vps13A, which interacts with Rab7 on LE/Lys, in lysosomal degradation was recently linked to its localization at the mitochondria‐LE/Lys interface …”