{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T02:34:57Z","timestamp":1793932497004,"version":"4.8.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Mitochondrial dysfunction and protein aggregation are central features of brain aging and Alzheimer\u2019s disease (AD). To define how AD seed proteins modulate these processes, we applied quantitative proteomics to sarkosyl-insoluble aggregates from\n                      <jats:italic>C. elegans<\/jats:italic>\n                      models of normal aging and from worms expressing human A\u03b2 or Tau transgenes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Normal aging produced a late-onset accrual of mitochondrial proteins within aggregates, implicating impaired energy metabolism and proteostasis collapse. A\u03b2 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: A\u03b2 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings place mitochondrial proteome collapse at the center of aging and AD-seeded pathology, distinguish A\u03b2- 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2025.1713391","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T06:32:25Z","timestamp":1768285945000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The aggregate proteome of Caenorhabditis elegans mitochondria implicates shared mechanisms of aging and Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"17","author":[{"given":"Sonu","family":"Pahal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akshatha","family":"Ganne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meenakshisundaram","family":"Balasubramaniam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sue T.","family":"Griffin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Shmookler Reis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinivas","family":"Ayyadevara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1007\/s00441-016-2463-1","article-title":"Mitochondrial lipids in neurodegeneration","volume":"367","author":"Aufschnaiter","year":"2016","journal-title":"Cell Tissue Res."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1111\/acel.12296","article-title":"Proteins in aggregates functionally impact multiple neurodegenerative disease models by forming proteasome-blocking complexes","volume":"14","author":"Ayyadevara","year":"2015","journal-title":"Aging Cell"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"924","DOI":"10.1111\/acel.12501","article-title":"Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls","volume":"15","author":"Ayyadevara","year":"","journal-title":"Aging Cell"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"3486","DOI":"10.18632\/aging.101141","article-title":"Proteins that accumulate with age in human skeletal-muscle aggregates contribute to declines in muscle mass and function in Caenorhabditis elegans","volume":"8","author":"Ayyadevara","year":"","journal-title":"Aging"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.isci.2019.09.026","article-title":"Aggregate interactome based on protein cross-linking interfaces predicts drug targets to limit aggregation in neurodegenerative diseases","volume":"20","author":"Balasubramaniam","year":"2019","journal-title":"iScience."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"108745","DOI":"10.1016\/j.isci.2023.108745","article-title":"Alzheimer\u2019s-specific brain amyloid interactome: neural-network analysis of intra-aggregate crosslinking identifies novel drug targets","volume":"27","author":"Balasubramaniam","year":"2023","journal-title":"iScience."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"e50094","DOI":"10.15252\/embr.202050094","article-title":"Systemic effects of mitochondrial stress","volume":"21","author":"Bar-Ziv","year":"","journal-title":"EMBO Rep."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"e50094","DOI":"10.15252\/embr.202050094","article-title":"Systemic effects of mitochondrial stress","volume":"21","author":"Bar-Ziv","year":"2020","journal-title":"EMBO Rep."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1091\/mbc.e10-08-0718","article-title":"Mitochondrial enzymes are protected from stress-induced aggregation by mitochondrial chaperones and the Pim1\/LON protease","volume":"22","author":"Bender","year":"2011","journal-title":"Mol. 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