ER ‐mitochondria contacts and cholesterol metabolism are disrupted by disease‐associated tau protein
Abstract: Abnormal tau protein impairs mitochondrial function, including transport, dynamics, and bioenergetics. Mitochondria interact with the endoplasmic reticulum (ER) via mitochondria‐associated ER membranes (MAMs), which coordinate and modulate many cellular functions, including mitochondrial cholesterol metabolism. Here, we show that abnormal tau loosens the association between the ER and mitochondria in vivo and in vitro. Especially, ER‐mitochondria interactions via vesicle‐associated membrane protein‐associated protein (VAPB)—protein tyrosine phosphatase‐interacting protein 51 (PTPIP51) are decreased in the presence of abnormal tau. Disruption of MAMs in cells with abnormal tau alters the levels of mitochondrial cholesterol and pregnenolone, indicating that conversion of cholesterol into pregnenolone is impaired. Opposite effects are observed in the absence of tau. Besides, targeted metabolomics reveals overall alterations in cholesterol‐related metabolites by tau. The inhibition of GSK3β decreases abnormal tau hyperphosphorylation and increases VAPB–PTPIP51 interactions, restoring mitochondrial cholesterol and pregnenolone levels. This study is the first to highlight a link between tau‐induced impairments in the ER‐mitochondria interaction and cholesterol metabolism.
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Bibliographic citation
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ER ‐mitochondria contacts and cholesterol metabolism are disrupted by disease‐associated tau protein ; day:04 ; month:07 ; year:2023 ; extent:31
EMBO reports / European Molecular Biology Organization ; (04.07.2023) (gesamt 31)
- Creator
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Szabo, Leonora
Cummins, Nadia
Paganetti, Paolo
Odermatt, Alex
Papassotiropoulos, Andreas
Karch, Celeste
Götz, Jürgen
Eckert, Anne
Grimm, Amandine
- DOI
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10.15252/embr.202357499
- URN
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urn:nbn:de:101:1-2023070515013026173592
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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14.08.2025, 10:57 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Szabo, Leonora
- Cummins, Nadia
- Paganetti, Paolo
- Odermatt, Alex
- Papassotiropoulos, Andreas
- Karch, Celeste
- Götz, Jürgen
- Eckert, Anne
- Grimm, Amandine
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