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 PMID:37828862  

Impaired mitophagosome-lysosome fusion mediates olanzapine-induced aging.

Xi Chen | Zhizhen Wang | Peng Zheng | Anjila Dongol | Yuanyi Xie | Xing Ge | Mingxuan Zheng | Xuemei Dang | Zehra Boz Seyhan | Nathan Nagaratnam | Yinghua Yu | Xu-Feng Huang
Aging cell | 2023

The lifespan of schizophrenia patients is significantly shorter than the general population. Olanzapine is one of the most commonly used antipsychotic drugs (APDs) for treating patients with psychosis, including schizophrenia and bipolar disorder. Despite their effectiveness in treating positive and negative symptoms, prolonged exposure to APDs may lead to accelerated aging and cognitive decline, among other side effects. Here we report that dysfunctional mitophagy is a fundamental mechanism underlying accelerated aging induced by olanzapine, using in vitro and in vivo (Caenorhabditis elegans) models. We showed that the aberrant mitophagy caused by olanzapine was via blocking mitophagosome-lysosome fusion. Furthermore, olanzapine can induce mitochondrial damage and hyperfragmentation of the mitochondrial network. The mitophagosome-lysosome fusion in olanzapine-induced aging models can be restored by a mitophagy inducer, urolithin A, which alleviates defective mitophagy, mitochondrial damage, and fragmentation of the mitochondrial network. Moreover, the mitophagy inducer ameliorated behavioral changes induced by olanzapine, including shortened lifespan, and impaired health span, learning, and memory. These data indicate that olanzapine impairs mitophagy, leading to the shortened lifespan, impaired health span, and cognitive deficits. Furthermore, this study suggests the potential application of mitophagy inducers as therapeutic strategies to reverse APD-induced adverse effects associated with accelerated aging.

Pubmed ID: 37828862

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This is a list of tools and resources that we have found mentioned in this publication.


Addgene (tool)

RRID:SCR_002037

Non-profit plasmid repository dedicated to helping scientists around the world share high-quality plasmids. Facilitates archiving and distributing DNA-based research reagents and associated data to scientists worldwide. Repository contains over 65,000 plasmids, including special collections on CRISPR, fluorescent proteins, and ready-to-use viral preparations. There is no cost for scientists to deposit plasmids, which saves time and money associated with shipping plasmids themselves. All plasmids are fully sequenced for validation and sequencing data is openly available. We handle the appropriate Material Transfer Agreements (MTA) with institutions, facilitating open exchange and offering intellectual property and liability protection for depositing scientists. Furthermore, we curate free educational resources for the scientific community including a blog, eBooks, video protocols, and detailed molecular biology resources.

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Applied Biosystems (tool)

RRID:SCR_005039

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FlowJo (tool)

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Software for single-cell flow cytometry analysis. Its functions include management, display, manipulation, analysis and publication of the data stream produced by flow and mass cytometers.

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QIAGEN (tool)

RRID:SCR_008539

A commercial organization which provides assay technologies to isolate DNA, RNA, and proteins from any biological sample. Assay technologies are then used to make specific target biomolecules, such as the DNA of a specific virus, visible for subsequent analysis.

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BD Biosciences (tool)

RRID:SCR_013311

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ThermoFisher Scientific EVOS M5000 Imaging System (tool)

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RRID:SCR_007341

Center that acquires, maintains, and distributes genetic stocks and information about stocks of the small free-living nematode Caenorhabditis elegans for use by investigators initiating or continuing research on this genetic model organism. A searchable strain database, general information about C. elegans, and links to key Web sites of use to scientists, including WormBase, WormAtlas, and WormBook are available.

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N2_(ancestral) (tool)

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Caenorhabditis elegans with name Caenorhabditis elegans wild isolate. from WB.

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