Abstract
A persistent accumulation of damaged mitochondria is part of prion disease pathogenesis. Normally, damaged mitochondria are cleared via a major pathway that involves the E3 ubiquitin ligase parkin and PTEN-induced kinase 1 (PINK1) that together initiate mitophagy, recognize and eliminate damaged mitochondria. However, the precise mechanisms underlying mitophagy in prion disease remain largely unknown. Using prion disease cell models, we observed PINK1-parkin-mediated mitophagy deficiency in which parkin depletion aggravated blocked mitochondrial colocalization with LC3-II-labeled autophagosomes, and significantly increased mitochondrial protein levels, which led to inhibited mitophagy. Parkin overexpression directly induced LC3-II colocalization with mitochondria and alleviated defective mitophagy. Moreover, parkin-mediated mitophagy was dependent on PINK1, since PINK1 depletion blocked mitochondrial Parkin recruitment and reduced optineurin and LC3-II proteins levels, thus inhibiting mitophagy. PINK1 overexpression induced parkin recruitment to the mitochondria, which then stimulated mitophagy. In addition, overexpressed parkin and PINK1 also protected neurons from apoptosis. Furthermore, we found that supplementation with two mitophagy-inducing agents, nicotinamide mononucleotide (NMN) and urolithin A (UA), significantly stimulated PINK1-parkin-mediated mitophagy. However, compared with NMN, UA could not alleviate prion-induced mitochondrial fragmentation and dysfunction, and neuronal apoptosis. These findings show that PINK1-parkin-mediated mitophagy defects lead to an accumulation of damaged mitochondria, thus suggesting that interventions that stimulate mitophagy may be potential therapeutic targets for prion diseases.
Highlights
Prion diseases are a group of chronic, fatal, neurodegenerative diseases that can infect humans and animals [1, 2]
Our previous results had shown that prion diseases are S4C, D) in N2a cells and revealed that N2a cells treated with characterized by morphological mitochondrial fragmentation PrP106-126 for 24 h had significantly inhibited parkin recruitment and dysfunction in the affected neurons [15, 28]
In order to detect mitophagy, the following two methods were used: (1) We took advantage of coral-derived protein Keima, within the acidic lysosome after mitophagy, mitochondrial matrix-targeted expression alleviated the inhibition of parkin recruitment induced by PrP106-126, but PTEN-induced kinase 1 (PINK1) deficiency enhanced the inhibition
Summary
Prion diseases are a group of chronic, fatal, neurodegenerative diseases that can infect humans and animals [1, 2]. Since the neurotoxicity of PrP106-126 was first reported in 1993 [4], numerous laboratories have used this peptide as an experimental model to investigate the molecular mechanisms of PrPSc neurotoxicity [5,6,7,8,9,10] This peptide maintains most of the pathogenic characteristics of PrPSc, including neurotoxicity, gliotrophic activity, proteinase-K resistance, and β-sheet structure. This peptide was reported to induce apoptotic death in primary cultures of hippocampal, cortical, and cerebellar neurons [11]. PrP106-126 is proved useful in clarifying the structural and physicochemical features underlying PrP neurotoxicity [10, 11]
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