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FMN reduces Amyloid-? toxicity in yeast by regulating redox status and cellular metabolism.

ABSTRACT: Alzheimer's disease (AD) is defined by progressive neurodegeneration, with oligomerization and aggregation of amyloid-? peptides (A?) playing a pivotal role in its pathogenesis. In recent years, the yeast Saccharomyces cerevisiae has been successfully used to clarify the roles of different human proteins involved in neurodegeneration. Here, we report a genome-wide synthetic genetic interaction array to identify toxicity modifiers of A?42, using yeast as the model organism. We find that FMN1, the gene encoding riboflavin kinase, and its metabolic product flavin mononucleotide (FMN) reduce A?42 toxicity. Classic experimental analyses combined with RNAseq show the effects of FMN supplementation to include reducing misfolded protein load, altering cellular metabolism, increasing NADH/(NADH?+?NAD+) and NADPH/(NADPH?+?NADP+) ratios and increasing resistance to oxidative stress. Additionally, FMN supplementation modifies Htt103QP toxicity and ?-synuclein toxicity in the humanized yeast. Our findings offer insights for reducing cytotoxicity of A?42, and potentially other misfolded proteins, via FMN-dependent cellular pathways.

SUBMITTER: Chen X

PROVIDER: S-EPMC7018843 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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FMN reduces Amyloid-β toxicity in yeast by regulating redox status and cellular metabolism.

Chen Xin X Ji Boyang B Hao Xinxin X Li Xiaowei X Eisele Frederik F Nyström Thomas T Petranovic Dina D

Nature communications 20200213 1

Alzheimer's disease (AD) is defined by progressive neurodegeneration, with oligomerization and aggregation of amyloid-β peptides (Aβ) playing a pivotal role in its pathogenesis. In recent years, the yeast Saccharomyces cerevisiae has been successfully used to clarify the roles of different human proteins involved in neurodegeneration. Here, we report a genome-wide synthetic genetic interaction array to identify toxicity modifiers of Aβ42, using yeast as the model organism. We find that FMN1, the ...[more]

PMID: 32054832

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Project description:Artesunate (ART) is a prominent anti-malarial with significant anti-cancer properties. Our previous studies showed that ART enhances lysosomal function and ferritin degradation, which was necessary for its anti-cancer properties. ART targeting to mitochondria also significantly improved its efficacy, but the effect of ART on mitophagy, an important cellular pathway that facilitates the removal of damaged mitochondria, remains unknown. Here, we first observed that ART mainly localizes in the mitochondria and its probe labeling revealed that it binds to a large number of mitochondrial proteins and causes mitochondrial fission. Second, we found that ART treatment leads to autophagy induction and the decrease of mitochondrial proteins. When autophagy is inhibited, the decrease of mitochondrial proteins could be reversed, indicating that the degradation of mitochondrial proteins is through mitophagy. Third, our results showed that ART treatment stabilizes the full-length form of PTEN induced putative kinase 1 (PINK1) on the mitochondria and activates the PINK1-dependent pathway. This in turn leads to the recruitment of Parkin, sequestosome 1 (SQSTM1), ubiquitin and microtubule-associated proteins 1A/1B light chain 3 (LC3) to the mitochondria and culminates in mitophagy. When PINK1 is knocked down, ART-induced mitophagy is markedly suppressed. Finally, we investigated the effect of mitophagy by ART on mitochondrial functions and found that knockdown of PINK1 alters the cellular redox status in ART-treated cells, which is accompanied with a significant decrease in glutathione (GSH) and increase in mitochondrial reactive oxidative species (mROS) and cellular lactate levels. Additionally, knockdown of PINK1 leads to a significant increase of mitochondrial depolarization and more cell apoptosis by ART, suggesting that mitophagy protects from ART-induced cell death. Taken together, our findings reveal the molecular mechanism that ART induces cytoprotective mitophagy through the PINK1-dependent pathway, suggesting that mitophagy inhibition could enhance the anti-cancer activity of ART.

Dataset Information

FMN reduces Amyloid-? toxicity in yeast by regulating redox status and cellular metabolism.

Publications

FMN reduces Amyloid-β toxicity in yeast by regulating redox status and cellular metabolism.

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