2. Academic Validation
  3. ER-mitochondria contacts and cholesterol metabolism are disrupted by disease-associated tau protein

ER-mitochondria contacts and cholesterol metabolism are disrupted by disease-associated tau protein

  • EMBO Rep. 2023 Jul 4;e57499. doi: 10.15252/embr.202357499.
Leonora Szabo 1 2,  Nadia Cummins 3,  Paolo Paganetti 4 5,  Alex Odermatt 6,  Andreas Papassotiropoulos 1 7,  Celeste Karch 8,  Jürgen Götz 3,  Anne Eckert 1 2,  Amandine Grimm 1 2 7
Affiliations

Affiliations

  • 1 Research Cluster, Molecular and Cognitive Neurosciences, Department of Biomedicine, University of Basel, Basel, Switzerland.
  • 2 Neurobiology Lab for Brain Aging and Mental Health, Psychiatric University Clinics, Basel, Switzerland.
  • 3 Clem Jones Centre for Ageing Dementia Research (CJCADR), Queensland Brain Institute (QBI), The University of Queensland, St Lucia, QLD, Australia.
  • 4 Laboratory for Aging Disorders, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
  • 5 Faculty for Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland.
  • 6 Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
  • 7 Life Sciences Training Facility, University of Basel, Basel, Switzerland.
  • 8 Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA.
PMID: 37401859 DOI: 10.15252/embr.202357499
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.

Keywords

GSK3β; cholesterol; endoplasmic reticulum; mitochondria; tau protein.

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