Iron Limitation Restores Autophagy and Increases Lifespan in the Yeast Model of Niemann-Pick Type C1

• Type: Article in International Scientific Journal
• Date: 2023

Authors

Martins, TS (Author) Other; Costa, RS (Author) Other; Vilaca, R (Author) Other; Carolina Lemos (Author) ICBAS; Teixeira, V (Author) Other; Pereira, C (Author) Other; Vitor Costa (Author) ICBAS

Journal

Title: International Journal Of Molecular Sciences

Vol. 24 No. 2335

Final page: 6221

ISSN: 1661-6596

Publisher: MDPI

Indexing

ISI Web of Knowledge - 0 Citations

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Other information

Authenticus ID: P-00Y-ASQ

DOI: 10.3390/ijms24076221

Abstract (EN): Niemann-Pick type C1 (NPC1) is an endolysosomal transmembrane protein involved in the export of cholesterol and sphingolipids to other cellular compartments such as the endoplasmic reticulum and plasma membrane. NPC1 loss of function is the major cause of NPC disease, a rare lysosomal storage disorder characterized by an abnormal accumulation of lipids in the late endosomal/lysosomal network, mitochondrial dysfunction, and impaired autophagy. NPC phenotypes are conserved in yeast lacking Ncr1, an orthologue of human NPC1, leading to premature aging. Herein, we performed a phosphoproteomic analysis to investigate the effect of Ncr1 loss on cellular functions mediated by the yeast lysosome-like vacuoles. Our results revealed changes in vacuolar membrane proteins that are associated mostly with vesicle biology (fusion, transport, organization), autophagy, and ion homeostasis, including iron, manganese, and calcium. Consistently, the cytoplasm to vacuole targeting (Cvt) pathway was increased in ncr1? increment cells and autophagy was compromised despite TORC1 inhibition. Moreover, ncr1? increment cells exhibited iron overload mediated by the low-iron sensing transcription factor Aft1. Iron deprivation restored the autophagic flux of ncr1? increment cells and increased its chronological lifespan and oxidative stress resistance. These results implicate iron overload on autophagy impairment, oxidative stress sensitivity, and cell death in the yeast model of NPC1.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 21