IFN-β rescues neurodegeneration by regulating mitochondrial fission via STAT5, PGAM5, and Drp1
(2021) In EMBO Journal 40(11).- Abstract
Mitochondrial homeostasis is essential for providing cellular energy, particularly in resource-demanding neurons, defects in which cause neurodegeneration, but the function of interferons (IFNs) in regulating neuronal mitochondrial homeostasis is unknown. We found that neuronal IFN-β is indispensable for mitochondrial homeostasis and metabolism, sustaining ATP levels and preventing excessive ROS by controlling mitochondrial fission. IFN-β induces events that are required for mitochondrial fission, phosphorylating STAT5 and upregulating PGAM5, which phosphorylates serine 622 of Drp1. IFN-β signaling then recruits Drp1 to mitochondria, oligomerizes it, and engages INF2 to stabilize mitochondria–endoplasmic reticulum (ER) platforms. This... (More)
Mitochondrial homeostasis is essential for providing cellular energy, particularly in resource-demanding neurons, defects in which cause neurodegeneration, but the function of interferons (IFNs) in regulating neuronal mitochondrial homeostasis is unknown. We found that neuronal IFN-β is indispensable for mitochondrial homeostasis and metabolism, sustaining ATP levels and preventing excessive ROS by controlling mitochondrial fission. IFN-β induces events that are required for mitochondrial fission, phosphorylating STAT5 and upregulating PGAM5, which phosphorylates serine 622 of Drp1. IFN-β signaling then recruits Drp1 to mitochondria, oligomerizes it, and engages INF2 to stabilize mitochondria–endoplasmic reticulum (ER) platforms. This process tethers damaged mitochondria to the ER to separate them via fission. Lack of neuronal IFN-β in the Ifnb–/– model of Parkinson disease (PD) disrupts STAT5-PGAM5-Drp1 signaling, impairing fission and causing large multibranched, damaged mitochondria with insufficient ATP production and excessive oxidative stress to accumulate. In other PD models, IFN-β rescues dopaminergic neuronal cell death and pathology, associated with preserved mitochondrial homeostasis. Thus, IFN-β activates mitochondrial fission in neurons through the pSTAT5/PGAM5/S622Drp1 pathway to stabilize mitochondria/ER platforms, constituting an essential neuroprotective mechanism.
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- author
- Tresse, Emilie ; Riera-Ponsati, Lluís ; Jaberi, Elham ; Sew, Wei Qi Guinevere ; Ruscher, Karsten LU and Issazadeh-Navikas, Shohreh
- organization
- publishing date
- 2021-06-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- ATP, hydroxydopamine, mitochondrial metabolism, Parkinson disease, ROS
- in
- EMBO Journal
- volume
- 40
- issue
- 11
- article number
- e106868
- publisher
- Oxford University Press
- external identifiers
-
- pmid:33913175
- scopus:85107259279
- ISSN
- 0261-4189
- DOI
- 10.15252/embj.2020106868
- language
- English
- LU publication?
- yes
- id
- b3ea7c07-d8d2-4d4d-aa90-ec172a53e370
- date added to LUP
- 2021-06-22 14:45:33
- date last changed
- 2024-10-07 01:12:03
@article{b3ea7c07-d8d2-4d4d-aa90-ec172a53e370, abstract = {{<p>Mitochondrial homeostasis is essential for providing cellular energy, particularly in resource-demanding neurons, defects in which cause neurodegeneration, but the function of interferons (IFNs) in regulating neuronal mitochondrial homeostasis is unknown. We found that neuronal IFN-β is indispensable for mitochondrial homeostasis and metabolism, sustaining ATP levels and preventing excessive ROS by controlling mitochondrial fission. IFN-β induces events that are required for mitochondrial fission, phosphorylating STAT5 and upregulating PGAM5, which phosphorylates serine 622 of Drp1. IFN-β signaling then recruits Drp1 to mitochondria, oligomerizes it, and engages INF2 to stabilize mitochondria–endoplasmic reticulum (ER) platforms. This process tethers damaged mitochondria to the ER to separate them via fission. Lack of neuronal IFN-β in the Ifnb<sup>–/–</sup> model of Parkinson disease (PD) disrupts STAT5-PGAM5-Drp1 signaling, impairing fission and causing large multibranched, damaged mitochondria with insufficient ATP production and excessive oxidative stress to accumulate. In other PD models, IFN-β rescues dopaminergic neuronal cell death and pathology, associated with preserved mitochondrial homeostasis. Thus, IFN-β activates mitochondrial fission in neurons through the pSTAT5/PGAM5/<sup>S622</sup>Drp1 pathway to stabilize mitochondria/ER platforms, constituting an essential neuroprotective mechanism.</p>}}, author = {{Tresse, Emilie and Riera-Ponsati, Lluís and Jaberi, Elham and Sew, Wei Qi Guinevere and Ruscher, Karsten and Issazadeh-Navikas, Shohreh}}, issn = {{0261-4189}}, keywords = {{ATP; hydroxydopamine; mitochondrial metabolism; Parkinson disease; ROS}}, language = {{eng}}, month = {{06}}, number = {{11}}, publisher = {{Oxford University Press}}, series = {{EMBO Journal}}, title = {{IFN-β rescues neurodegeneration by regulating mitochondrial fission via STAT5, PGAM5, and Drp1}}, url = {{http://dx.doi.org/10.15252/embj.2020106868}}, doi = {{10.15252/embj.2020106868}}, volume = {{40}}, year = {{2021}}, }