ORIGINAL RESEARCH article
Front. Aging Neurosci.
Sec. Cellular and Molecular Mechanisms of Brain-aging
This article is part of the Research TopicMitochondrial Dysfunction in Cellular and Molecular Mechanisms of Brain AgingView all articles
The aggregate proteome of C. elegans mitochondria implicates shared mechanisms of aging and Alzheimer's disease
Provisionally accepted
Sonu Pahal1,2
Akshatha Ganne2
Meenakshisundaram Balasubramaniam1,2
Sue T Griffin2,3
Robert Joseph Shmookler Reis2,3
Srinivas Ayyadevara1,2,3*- 1University of Arkansas at Little Rock, Little Rock, United States
- 2University of Arkansas for Medical Sciences, Little Rock, United States
- 3Geriatrics/Medicine, Central Arkansas Veterans Healthcare System, Veterans Health Administration, United States Department of Veterans Affairs, Little Rock, arkansas, United States
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
Background: Mitochondrial dysfunction and protein aggregation are central features of brain aging and Alzheimer's disease (AD). To define how AD seed proteins modulate these processes, we applied quantitative proteomics to sarkosyl-insoluble aggregates from C. elegans models of normal aging and from worms expressing human Aβ or tau transgenes. Results: Normal aging produced a late-onset accrual of mitochondrial proteins within aggregates, implicating impaired energy metabolism and proteostasis collapse. Aβ expression caused a striking expansion and included glycolytic enzymes, tricarboxylic acid cycle components, ribosomal proteins, and trafficking factors, consistent with broad proteostatic and bioenergetic stress, largely overlapping with aging-associated species, yet advanced in onset. Tau expression yielded a smaller set enriched for cytoskeletal, vesicular, and nuclear pore components. Post-translational modifications (4-HNE adducts, phosphorylation, acetylation, methionine oxidation) revealed distinct trajectories: Aβ imposed early oxidative and phosphorylation burden, whereas Tau and aging showed midlife PTM peaks consistent with delayed proteostasis collapse. Cross-species comparison revealed 68 insoluble proteins shared between worm models and human AD brain aggregates. From these, 17 conserved metabolic, chaperone, and trafficking proteins were prioritized by network metrics and validated functionally: RNAi knockdowns aggravated paralysis or impaired chemotaxis, confirming their functional importance. Conclusions: These findings place mitochondrial proteome collapse at the center of aging and AD-seeded pathology, distinguish Aβ-and Tau-driven proteotoxic routes, and nominate a conserved panel of aggregation-prone proteins as mechanistic drivers and candidate biomarkers for early detection and intervention in AD.
Keywords: Aging, Alzheimer disease, C.elegans, Mitochondria, neurodegeneration, protein aggregation
Received: 25 Sep 2025; Accepted: 28 Nov 2025.
Copyright: © 2025 Pahal, Ganne, Balasubramaniam, Griffin, Shmookler Reis and Ayyadevara. 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: Srinivas Ayyadevara
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.