Olanzapine impairs mitophagy to promote cellular senescence and accelerate ageing
Creators: name: Chen, Xi
Publisher: name: University of Wollongong
Year: 2025
Subjects: classificationCode: 3209
subject: Neurosciences
subject: FOS: Clinical medicine

description: Schizophrenia is a severe mental disorder that affects about 1% of the population worldwide. According to previous research, patients with schizophrenia have approximately 14.5 years less life expectancy than the general population. Moreover, structural brain change (cortical thinning) and cognitive decline have been reported in patients with schizophrenia, suggestive of brain ageing. Abnormal levels of systemic ageing-related biomarkers have been reported in schizophrenia, suggesting an acceleration of the ageing process. However, the reason for these changes in patients with schizophrenia is unclear. Antipsychotic drugs (APDs) are the cornerstone of medication for schizophrenia, relieving both the positive and negative psychotic symptoms. Chronic administration of APDs is associated with severe cognitive impairment and ageing-related cortical thinning in both patients with schizophrenia and animal studies. Therefore, the aim of this study was to investigate whether olanzapine, one of the most commonly used APDs, accelerates ageing and affects the associated changes.Mitophagy is a biological process that eliminates damaged mitochondria. Defective mitophagy causes the accumulation of damaged mitochondria which is the mechanism underlying the pathology of ageing and ageing-related diseases. The data in Chapters 2 and 3 show that impaired mitophagy is the underlying mechanism by which olanzapine accelerates ageing, using in vitro and in vivo (Caenorhabditis elegans, C. elegans) models. Olanzapine impairs mitophagy by blocking the fusion of mitophagosomes with lysosomes. Moreover, olanzapine damages mitochondria and causes hyperfragmentation of the mitochondrial network. Urolithin A (UA) is a mitophagy inducer, which is beneficial for lifespan extension and cognitive performance. Here, I report that UA ameliorates lifespan shortening, healthspan impairment, and deficits in olfactory-associated learning and memory in C. elegans treated with olanzapine. Moreover, UA alleviates mitochondrial damage, ameliorates fragmentation of the mitochondrial network, and enhances mitophagic activity through mitophagosome-lysosome fusion in the presence of olanzapine. These data indicate that olanzapine shortens lifespan, impairs healthspan, and causes cognitive deficits, which are attributed to mitophagy impairment.Functional lysosomes and the formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes are essential for the fusion of mitophagosomes with lysosomes in mitophagy. After observing the perturbed fusion induced by olanzapine, I investigated whether olanzapine affects lysosomal function and SNARE complex formation. The data in Chapter 4 show that olanzapine increases lysosomal luminal pH and decreases degradative capacity. Furthermore, olanzapine interferes with the co-localization of syntaxin 17 (STX17) and synaptosome-associated protein 29 (SNAP29), two SNARE proteins that participate in complex formation. Therefore, defective mitophagy induced by olanzapine may be associated with lysosomal dysfunction and hampered SNAP29/STX17 interaction.Defective mitophagy promotes the onset of cellular senescence, triggering ageing and ageing-related diseases, which suggests that olanzapine might induce cellular senescence by impairing mitophagy. I found that olanzapine administration led to increased mRNA expression of cellular senescence-related genes and higher senescence-associated β-galactosidase (SA-β-Gal) activity in both primary cultured cortical neurons and the piriform cortex in rats (Chapters 4 and 5). Rats treated with olanzapine have an increased number of microglia in the piriform cortex. Moreover, the microglia appear to be the main source of higher SA-β-Gal expression in the brains of aged mice. In addition, analysis of differentially expressed genes in the tissue of mice treated with olanzapine revealed the crosstalk between the cellular senescence and mitophagy pathways, suggesting that olanzapine interferes with cellular senescence and mitophagy in both cellular and animal models.In conclusion, this study revealed that the effect of olanzapine on the acceleration of ageing is dependent on defective mitophagy via perturbed fusion of mitophagosomes with lysosomes. Also, olanzapine impairs lysosomal function and the interaction between SNAP29 and STX17, which might inhibit the completion of mitophagy and subsequently induce cellular senescence. Therefore, there is an urgent need to discover potential therapeutics, such as mitophagy inducers, to counteract the detrimental effects of olanzapine on cellular senescence and acceleration of ageing.