IFN-β rescues neurodegeneration by regulating mitochondrial fission via STAT5, PGAM5, and Drp1.
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/S622 Drp1 pathway to stabilize mitochondria/ER platforms, constituting an essential neuroprotective mechanism.
['Tresse|Emilie|E|', 'Riera-Ponsati|Lluís|L|', 'Jaberi|Elham|E|', 'Sew|Wei Qi Guinevere|WQG|', 'Ruscher|Karsten|K|', 'Issazadeh-Navikas|Shohreh|S|0000-0003-0369-424X']
D000818:Animals D002460:Cell Line D045744:Cell Line, Tumor D034281:Dynamins D000080865:Formins D016899:Interferon-beta D051379:Mice D008928:Mitochondria D063154:Mitochondrial Dynamics D009474:Neurons D010300:Parkinson Disease D010749:Phosphoprotein Phosphatases D050799:STAT5 Transcription Factor
ATP ROS Parkinson disease hydroxydopamine mitochondrial metabolism