[Epigenetic regulator DOT1L controls neuronal amyloid pre-cursor protein expression via the p38 mediated mitochondrial fission-fusion homeostasis axis].

Authors

Yumin Zhang, Feiyu Zhu, Xiaotian Wu, Zhansong Li, Peng Huang, Yanpan Gao, Linghui Zeng

Published in

Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences. Pages 1-13. Jun 29, 2026. Epub Jun 29, 2026.

Abstract

To investigate the regulatory role of epigenetic regulator disruptor of telomeric silencing 1-like (DOT1L) and its mediated histone H3 lysine 79 (H3K79) methylation in modulating neuronal amyloid precursor protein (APP) expression, and to elucidate the underlying mechanisms involving mitochondrial homeostasis and the upstream p38 kinase.
Alzheimer's disease (AD) models were established using APP/presenilin-1 (APP/PS1) double-transgenic mice and N2a cells overexpressing the human Swedish mutant APP (N2a-APPswe). Immunofluorescence staining was employed to assess DOT1L expression and localization in mouse brain tissues. N2a-APPswe cells were treated with the DOT1L-specific inhibitor EPZ5676 and divided into four groups: blank control, solvent control, DOT1L inhibitor, and DOT1L inhibitor plus p38 agonist (Gynostemma pentaphyllum extract). Western blotting was performed to measure the phosphorylation levels of DRP1 at Ser616 and Ser637 (key mitochondrial fission regulators), the levels of autophagy-related proteins p62 and the LC3-Ⅱ/LC3-Ⅰ ratio, the phosphorylation level of p38, as well as the expression of APP and APP-processing proteins BACE1 and PS1. Real-time quantitative polymerase chain reaction was used to detect mRNA levels of APP and genes involved in mitochondrial fission and fusion. Proteomics data were systematically analyzed through Gene Ontology analysis, WikiPathways enrichment analysis, and STRING protein-protein interaction network analysis to identify key signaling pathways. Mitochondrial morphology was evaluated by Mito-Tracker fluore-scence staining to measure average branch length.
DOT1L expression was signifi-cantly reduced in neurons of APP/PS1 mice compared to wild-type controls. DOT1L inhibition led to decreased H3K79me2 levels (P<0.01), accompanied by a marked increase in APP protein expression (P<0.01), although APP mRNA levels were reduced (P<0.01). Proteomics analysis revealed that differentially expressed proteins were highly enriched in the mitochondrial electron transport chain. Compared with the solvent control, the DOT1L inhibitor group showed inhibited mitochondrial fission, as evidenced by decreased p-DRP1 (Ser616), increased p-DRP1 (Ser637), downregulated MIEF1 mRNA, upregulated MFN1 mRNA (all P<0.05), and increased average mitochondrial branch length (P<0.05), along with reduced p-p38 levels (P<0.05). Co-administration of the p38 agonist significantly reversed these mitochondrial dynamics abnormalities (all P<0.05) and attenuated the abnormally elevated protein levels of APP, BACE1, and PS1 (P<0.05) compared to the DOT1L inhibitor group.
DOT1L maintains normal mito-chondrial fission and functional homeostasis through regulation of the p38 signaling pathway, thereby modulating APP expression.

PMID:
42392996
Bibliographic data and abstract were imported from PubMed on 03 Jul 2026.

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