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. image Endoplasmic reticulum (ER)—mitochondria coupling regulates many cellular functions, including mitochondrial cholesterol metabolism. This study shows that abnormal tau protein disrupts ER—mitochondria contacts, impairing cholesterol metabolism and pregnenolone synthesis within mitochondria. Contact points between the endoplasmic reticulum (ER) and mitochondria are decreased in the presence of P301L mutant tau protein. P301Ltau disturbs cholesterol metabolism and its conversion to pregnenolone within mitochondria. P301Ltau expression and tau knockout show opposite effects on ER‐mitochondria association and cholesterol metabolism. The P301Ltau‐induced disruption of ER‐mitochondria contacts and cholesterol homeostasis is restored by GSK3β inhibition.