REVIEW article
Front. Cell. Neurosci.
Sec. Cellular Neuropathology
Volume 19 - 2025 | doi: 10.3389/fncel.2025.1636185
This article is part of the Research TopicEmerging Mechanisms in Neuroinflammation: Potential Therapeutic Targets for Neurodegenerative DiseasesView all 8 articles
Spatiotemporal crosstalk among mitochondrial dynamics, NLRP3 1 inflammasome activation, and histone lactylation drives α-synuclein pathology in 2 prodromal Parkinson's disease
Provisionally accepted
- 1Heilongjiang University of Chinese Medicine, Harbin, China
- 2Institute of Acupuncture and Moxibustion, Heilongjiang Academy of Traditional Chinese Medicine,, Harbin, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
This article conducts a systematic search of literature in the fields of 9 neuroscience, cell biology, immunometabolism, etc. from 1990 to 2025, with 10 PubMed/WebofScience as the core database. Experimental and clinical studies 11 covering the core mechanisms of the preprophase of PD (mitochondrial imbalance 12 →NLRP3 activation→lactation modification→α -SYN pathology) were included, and 13 non-interaction mechanisms and clinical-phase studies were excluded. The 14 pathological interaction network of mitochondrial dynamic imbalance, lysosomes - 15 mitochondrial interaction disorder and neuroinflammation in Parkinson's disease (PD) 16 was explained. Construct a three-dimensional pathological network of 17 "energy-inflammation-protein homeostasis" to provide a theoretical basis for early 18 intervention.The imbalance of mitochondrial fission/fusion leads to the accumulation 19 of fragmented mitochondria, triggering energy metabolism disorders and oxidative 20 stress; abnormal aggregation of α-synuclein (α-syn) disrupts 21 mitochondrial-endoplasmic reticulum membrane (MAM) calcium signaling, 22 upregulates Miro protein to inhibit mitochondrial autophagy clearance, forming a 23 vicious cycle of neuronal damage. Defects in the PINK1/Parkin pathway and LRRK2 24 mutations interfere with the turnover of mitochondrial fission complexes, causing 25 mtDNA leakage, activating the NLRP3 inflammasome, and driving 26 neuroinflammatory cascades. Additionally, lysosomal dysfunction caused by GBA1 27 mutations exacerbates mitochondrial quality control defects through Rab7 activity 28 imbalance. Abnormal lactate metabolism may influence inflammasome activity 29 through epigenetic regulation, but its role in PD needs further validation. Based on the 30 above mechanisms, a diagnostic strategy for the prodromal phase integrating dynamic 31 monitoring of mitochondrial fragmentation index, lysosomal function markers, and 32 inflammatory factors is proposed, along with new intervention directions targeting 33 Drp1, NLRP3, and the lysosome-mitochondria interface.
Keywords: Parkinson's disease, Prodromal phase, mitochondrial dynamics, NLRP3 inflammasome, lactylation modification
Received: 27 May 2025; Accepted: 03 Sep 2025.
Copyright: © 2025 Lv, Chen, Liu, Zhang, Wang, Wang and Bai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Shun Wang, Heilongjiang University of Chinese Medicine, Harbin, China
Yan Bai, Institute of Acupuncture and Moxibustion, Heilongjiang Academy of Traditional Chinese Medicine,, Harbin, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.