SMALL MOLECULE PROMOTES MITOCHONDRIAL BIOGENESIS BY UPREGULATING PGC1α IN SH-SY5Y CELLS AND PRIMARY NEURONAL CELLS

Abstract

Pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD), Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis are proposed by mitochondrial abnormalities. Under pathological and physiological conditions regulatory mechanisms of mitochondrial biogenesis is unknown. Transcriptional regulatory network for mitochondrial biogenesis from peroxisome proliferator-activated receptor coactivator-1 (PGC-1) family plays a central role. Mitochondrial biogenesis proteins was studied by western blot and immunofluorescence, while as measurement of reactive oxygen species and mitochondrial biogenesis was studied by flow cytometer and integrity of mitochondrial was studied by electron microscope. IIIM 533 enhances mitochondrial biogenesis through upregulation of PGC-1α which further enhances the activities of NRF1 and NRF2 in differentiated SHSY-5Y cells and murine primary neurons. Furthermore, activation of NRF1 and NRF2 leads to the activation of tfam, mitochondrial specific proteins mitochondrial DNA replication and transcription. After mechanistically confirming the induction of mitochondrial biogenesis by IIIM 533, we further examined its effect on disturbances in mitochondrial dynamics during amyloid beta neurotoxicity. Surprisingly SHSY-5Y cells and murine primary neurons pre-treated with IIIM 533 attenuated mitochondrial damage by activating PGC-1α. In order to demonstrate the involvement of IIIM 533, knock down of PGC-1α increased amyloid beta induced mitochondrial damage. IIIM 533 also rescued SHSY-5Y cells and murine primary neurons from mitochondrial membrane potential loss, reduced elevated ROS and increased cell viability against amyloid beta insult. Based on these data IIIM 533 can be further investigated as a potential anti Alzheimer therapeutic lead.