Related Experiment Video
Updated: Jun 20, 2025
Protection of H9c2 Myocardial Cells from Oxidative Stress by Crocetin via PINK1/Parkin Pathway-Mediated Mitophagy
Published on: May 26, 2023
Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation
Michael O Isei1, Meredith Crockett1, Emily Chen1
1University of Rochester, Department of Anesthesiology & Perioperative Medicine, Rochester, New York, USA.
Abstract:
Neurodegenerative diseases are often characterized by mitochondrial dysfunction. In Alzheimer's disease, abnormal tau phosphorylation disrupts mitophagy, a quality control process through which damaged organelles are selectively removed from the mitochondrial network. The precise mechanism through which this occurs remains unclear. Previously, we showed that tau which has been mutated at Thr-231 to glutamic acid to mimic an Alzheimer's-relevant phospho-epitope expressed early in disease selectively inhibits oxidative stress-induced mitophagy in C. elegans. Here, we use immortalized mouse hippocampal neuronal cell lines to extend that result into mammalian cells. Specifically, we show that phosphomimetic tau at Ser-396/404 (EC) or Thr-231/Ser-235 (EM) partly inhibits mitophagy induction by paraquat, a potent inducer of mitochondrial oxidative stress. Moreover, a combination of immunologic and biochemical approaches demonstrates that the levels of the mitophagy receptor FKBP8, significantly decrease in response to paraquat in cells expressing EC or EM tau mutants, but not in cells expressing wildtype tau. In contrast, paraquat treatment results in a decrease in the levels of the mitophagy receptors FUNDC1 and BNIP3 in the presence of both wildtype tau and the tau mutants. Interestingly, FKBP8 is normally trafficked to the endoplasmic reticulum during oxidative stress induced mitophagy, and our results support a model where this trafficking is impacted by disease-relevant tau, perhaps through a direct interaction. We provide new insights into the molecular mechanisms underlying tau pathology in Alzheimer's disease and highlight FKBP8 receptor as a potential target for mitigating mitochondrial dysfunction in neurodegenerative diseases.
Insights
Abnormal tau phosphorylation in Alzheimer's disease impairs mitophagy, the process of clearing damaged mitochondria. This study shows disease-relevant tau mutants disrupt mitophagy receptor FKBP8 levels in mouse neurons, suggesting FKBP8 as a therapeutic target.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Neurodegenerative diseases, including Alzheimer's disease (AD), are linked to mitochondrial dysfunction.
- Abnormal tau phosphorylation is a hallmark of AD and disrupts mitophagy, a crucial cellular quality control mechanism for removing damaged mitochondria.
- The exact molecular mechanisms by which tau pathology interferes with mitophagy remain largely unknown.
Purpose of the Study:
- To investigate the role of disease-relevant tau phosphorylation in inhibiting mitophagy in mammalian neuronal cells.
- To identify specific mitophagy receptors affected by tau mutants during oxidative stress.
- To elucidate the potential molecular interactions between tau and mitophagy pathways.
Main Methods:
- Utilized immortalized mouse hippocampal neuronal cell lines.
- Expressed phosphomimetic tau mutants (EC and EM) mimicking AD-relevant phosphorylation sites.
- Induced mitochondrial oxidative stress using paraquat.
- Employed immunologic and biochemical approaches to quantify mitophagy receptor levels (FKBP8, FUNDC1, BNIP3).
Main Results:
- Phosphomimetic tau mutants (EC, EM) partially inhibited paraquat-induced mitophagy.
- Paraquat treatment led to decreased FKBP8 levels in cells expressing EC or EM tau, but not wildtype tau.
- FUNDC1 and BNIP3 levels decreased with paraquat treatment in both wildtype and mutant tau-expressing cells.
- Disease-relevant tau appears to impact the trafficking of FKBP8 to the endoplasmic reticulum during mitophagy.
Conclusions:
- Disease-associated tau phosphorylation partially inhibits mitophagy in mammalian neurons.
- The mitophagy receptor FKBP8 is selectively downregulated in the presence of disease-relevant tau mutants during oxidative stress.
- Tau pathology may interfere with FKBP8 trafficking, contributing to mitochondrial dysfunction in Alzheimer's disease.
- FKBP8 presents a potential therapeutic target for mitigating mitochondrial dysfunction in neurodegenerative conditions.
Related Concept Videos
01:22PI3K/mTOR/AKT Signaling Pathway
02:54Protein Kinases and Phosphatases
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
01:19Translocation of Proteins into the Mitochondria
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
01:02Phosphorylation
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
02:26NF-κB-dependent Signaling Pathway
NF-κB-dependent Signaling Mechanism
The...
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...