ATF5-regulated Mitochondrial Unfolded Protein Response Attenuates Neuronal Damage in Epileptic Rat by Reducing...

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Endoplasmic reticulum (ER) stress contributes to neuronal injury during seizures.
• Mitochondrial reactive oxygen species (ROS) are linked to ER stress, and activating transcription factor 5 (ATF5) regulates the mitochondrial unfolded protein response (mtUPR).
• The precise role of ATF5-regulated mtUPR in epilepsy-related ER stress and neuronal damage is unclear.

Purpose of the Study:

• To investigate the neuroprotective effects of ATF5-regulated mtUPR in a rat model of pilocarpine-induced epilepsy.
• To elucidate the underlying mechanisms involving ER stress and mitochondrial ROS.

Main Methods:

• Utilized a rat model of pilocarpine-induced epilepsy.
• Manipulated ATF5 expression using lentivirus infection (upregulation and downregulation).
• Assessed neuronal damage, apoptosis, ER stress markers (GRP78, PERK, ATF4, CHOP), mtUPR components (HSP60, ClpP), mitochondrial ROS levels, and apoptosis-related proteins (BCL2, BAX, cleaved-caspase-3).
• Administered the antioxidant mito-TEMPO to evaluate its protective effects.

Main Results:

• ATF5 upregulation attenuated seizures-induced neuronal damage and apoptosis, while downregulation exacerbated these effects.
• ATF5 upregulation enhanced mtUPR, reduced mitochondrial ROS, and suppressed ER stress markers.
• ATF5 upregulation decreased pro-apoptotic proteins (BAX, cleaved-caspase-3) and increased anti-apoptotic protein (BCL2).
• Mito-TEMPO mitigated the detrimental effects of ATF5 downregulation by reducing mitochondrial ROS.

Conclusions:

• ATF5-regulated mtUPR exerts significant neuroprotective effects against seizures in an epilepsy model.
• The protective mechanism involves reducing mitochondrial ROS, thereby alleviating ER stress and neuronal apoptosis.
• Targeting ATF5-mediated mtUPR represents a potential therapeutic strategy for epilepsy.