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Alves, F.* ; Lane, D.* ; Wahida, A. ; Jakaria, M.* ; Kalinowski, P.* ; Southon, A.* ; Belaidi, A.A.* ; Samperi-Esteve, T.* ; Nguyen, T.P.M.* ; Lei, P.* ; Krueger, M.* ; Mueller, S.* ; Conrad, M. ; Agarwal, P.* ; Leurgans, S.E.* ; Schneider, J.* ; Bush, A.I.* ; Ayton, S.*

Aberrant mitochondrial metabolism in Alzheimer's disease links energy stress with ferroptosis.

Adv. Sci., DOI: 10.1002/advs.202504175:e04175 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Alzheimer's disease (AD) is defined by β-amyloid plaques and tau-containing neurofibrillary tangles, but the ensuing cellular derangements that culminate in neurodegeneration remain elusive. Here, a mechanistic link between two AD pathophysiological hallmarks: energy insufficiency and oxidative stress is revealed. It is demonstrated that mitochondrial function and glutathione (GSH) flux are coupled, impacting neuronal ferroptosis susceptibility. Analysis of proteomic data from the inferior temporal cortex of 625 subjects along a continuum of clinical and pathological changes in AD, reveals a prominent depletion of mitochondrial proteins. Biogenetic insufficiency in AD is reflected by a concurrent loss of GSH, which requires 2 ATP for its synthesis, and genetic and pharmacologic ATP depletion models confirm that ATP is rate-limiting for GSH. Accordingly, an unbiased association analysis uncovers mitochondrial proteins in positive correlation with total GSH (t-GSH) in AD subjects. But mitochondria also consume GSH via the SLC25A39 transporter. It is found that mitochondrial inhibition either increases or decreases ferroptosis susceptibility in cellular models, depending on contextual factors that dictate whether mitochondria act as a net GSH producer or consumer, respectively. Mitochondria therefore control GSH flux, and loss of energy output is consequently demonstrated as a liability for ferroptosis in AD.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Atp ; Alzheimer's Disease ; Bioenergetics ; Ferroptosis ; Glutathione ; Mitochondria ; Neurodegeneration; Cognitive Impairment; Rush Memory; Glutathione; Brain; Iron; Homeostasis; Reveals
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 2198-3844
e-ISSN 2198-3844
Zeitschrift Advanced science
Quellenangaben Band: , Heft: , Seiten: , Artikelnummer: e04175 Supplement: ,
Verlag Wiley
Verlagsort Weinheim
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-506900-001
Förderungen
Operational Infrastructure Support Grant
Victorian Government
National Institute of Aging
National Health and Medical Research Council
DOI 10.1002/advs.202504175
WOS ID 001524102800001
Scopus ID 105009881395
PubMed ID 40625200
Erfassungsdatum 2025-07-16
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