RESUMO

Lipid-related disorders, which primarily affect metabolic tissues, including adipose tissue and the liver are associated with alterations in lysosome homeostasis. Obesity is one of the more prevalent diseases, which results in energy imbalance within metabolic tissues and lysosome dysfunction. Less frequent diseases include Niemann-Pick type C (NPC) and Gaucher diseases, both of which are known as Lysosomal Storage Diseases (LSDs), where lysosomal dysfunction within metabolic tissues remains to be fully characterized. Adipocytes and hepatocytes share common pathways involved in the lysosome-autophagic axis, which are regulated by the function of cathepsins and CD36, an immuno-metabolic receptor and display alterations in lipid diseases, and thereby impacting metabolic functions. In addition to intrinsic defects observed in metabolic tissues, cells of the immune system, such as B cells can infiltrate adipose and liver tissues, during metabolic imbalance favoring inflammation. Moreover, B cells rely on lysosomes to promote the processing and presentation of extracellular antigens and thus could also present lysosome dysfunction, consequently affecting such functions. On the other hand, growing evidence suggests that cells accumulating lipids display defective inter-organelle membrane contact sites (MCSs) established by lysosomes and other compartments, which contribute to metabolic dysfunctions at the cellular level. Overall, in this review we will discuss recent findings addressing common mechanisms that are involved in lysosome dysregulation in adipocytes and hepatocytes during obesity, NPC, and Gaucher diseases. We will discuss whether these mechanisms may modulate the function of B cells and how inter-organelle contacts, emerging as relevant cellular mechanisms in the control of lipid homeostasis, have an impact on these diseases.

RESUMO

Parkinson's disease (PD) is a highly prevalent neurodegenerative condition. The disease involves the progressive degeneration of dopaminergic neurons located in the substantia nigra pars compacta. Among late-onset, familial forms of Parkinson are cases with mutations in the PARK17 locus encoding the vacuolar protein sorting 35 (Vps35), a subunit of the retromer complex. The retromer complex is composed of a heterotrimeric protein core (Vps26-Vps35-Vps29). The best-known role of retromer is the retrieval of cargoes from endosomes to the Golgi complex or the plasma membrane. However, recent literature indicates that retromer performs roles associated with lysosomal and mitochondrial functions and degradative pathways such as autophagy. A common point mutation affecting the retromer subunit Vps35 is D620N, which has been linked to the alterations in the aforementioned cellular processes as well as with neurodegeneration. Here, we review the main aspects of the malfunction of the retromer complex and its implications for PD pathology. Besides, we highlight several controversies still awaiting clarification.

Assuntos

RESUMO

Aminochrome has been reported to induce lysosomal dysfunction by inhibiting the vacuolar H-type ATPase localized in lysosome membrane. DT-diaphorase has been proposed to prevent aminochrome neurotoxicity but it is unknown whether this enzyme prevents aminochrome-induced lysosomal dysfunction. In the present study, we tested the protective role of DT-diaphorase in lysosomal dysfunction by generating a cell line (SH-SY5YsiNQ7) with a stable expression of a siRNA against DT-diaphorase with only 10% expression of mRNA enzyme. The cells differentiated with retinoic acid and 12-o-tetradecanoylphorbol-13-acetate show a significant increase in the expression of tyrosine hydroxylase, vesicular monoamine transporter-2, and dopamine transporter. The incubation of SH-SY5YsiNQ7 cells with 10 µM aminochrome resulted in a significant decrease of lysosome pH determined by using acridine orange, while aminochrome has no effect on SH-SY5Y cells. These results support the proposed protective role of DT-diaphorase against aminochrome-induced lysosomal dysfunction.

Assuntos