Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation.
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 thro...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2025-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0307358 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841555637981413376 |
|---|---|
| author | Michael O Isei Meredith Crockett Emily Chen Joel Rodwell-Bullock Trae Carroll Peter A Girardi Keith Nehrke Gail V W Johnson |
| author_facet | Michael O Isei Meredith Crockett Emily Chen Joel Rodwell-Bullock Trae Carroll Peter A Girardi Keith Nehrke Gail V W Johnson |
| author_sort | Michael O Isei |
| collection | DOAJ |
| description | 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 Caenorhabditis 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. |
| format | Article |
| id | doaj-art-e02ab10d97034b4cbbd6245975f82c4c |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-e02ab10d97034b4cbbd6245975f82c4c2025-01-08T05:31:50ZengPublic Library of Science (PLoS)PLoS ONE1932-62032025-01-01201e030735810.1371/journal.pone.0307358Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation.Michael O IseiMeredith CrockettEmily ChenJoel Rodwell-BullockTrae CarrollPeter A GirardiKeith NehrkeGail V W JohnsonNeurodegenerative 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 Caenorhabditis 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.https://doi.org/10.1371/journal.pone.0307358 |
| spellingShingle | Michael O Isei Meredith Crockett Emily Chen Joel Rodwell-Bullock Trae Carroll Peter A Girardi Keith Nehrke Gail V W Johnson Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation. PLoS ONE |
| title | Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation. |
| title_full | Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation. |
| title_fullStr | Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation. |
| title_full_unstemmed | Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation. |
| title_short | Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation. |
| title_sort | tau phosphorylation suppresses oxidative stress induced mitophagy via fkbp8 receptor modulation |
| url | https://doi.org/10.1371/journal.pone.0307358 |
| work_keys_str_mv | AT michaeloisei tauphosphorylationsuppressesoxidativestressinducedmitophagyviafkbp8receptormodulation AT meredithcrockett tauphosphorylationsuppressesoxidativestressinducedmitophagyviafkbp8receptormodulation AT emilychen tauphosphorylationsuppressesoxidativestressinducedmitophagyviafkbp8receptormodulation AT joelrodwellbullock tauphosphorylationsuppressesoxidativestressinducedmitophagyviafkbp8receptormodulation AT traecarroll tauphosphorylationsuppressesoxidativestressinducedmitophagyviafkbp8receptormodulation AT peteragirardi tauphosphorylationsuppressesoxidativestressinducedmitophagyviafkbp8receptormodulation AT keithnehrke tauphosphorylationsuppressesoxidativestressinducedmitophagyviafkbp8receptormodulation AT gailvwjohnson tauphosphorylationsuppressesoxidativestressinducedmitophagyviafkbp8receptormodulation |