Brain uncoupling protein-2 mediates neuronal survival by leptin against mitochondrial dysfunction and ATP deficiency

Abstract

OBJECTIVE: To determine neuroprotective properties of neuronal uncoupling protein-2 (UCP2) and leptin under MPP1-induced oxidative stress and mitochondrial dysfunction. BACKGROUND: Mitochondrial dysfunction, ATP deficiency, and oxidative stress are associated with Parkinson’s disease (PD). UCPs delink ATP production from oxidative phosphorylation in mitochondria to reduce oxidative stress. UCP2 is expressed in brain. Leptin regulates energy homeostasis and metabolism, and is neuroprotective against apoptosis. We observed induction of UCP2 expression after leptin treatment in neuronal cultures. We hypothesize that leptin may preserve neuronal energy levels by modulating mitochondrial efficiency and ATP production via UCPs. METHODS: Neuroprotective effects of leptin were studied in MPP1-induced mitochondrial dysfunction and oxidative stress in SH-SY5Y cells. UCP2 was stably knocked down by microRNA. Cells were exposed to MPP1 (0.5 mM) with and without leptin (30 lg/ml) for 24 hr. ATP levels were monitored by luciferase assay; level of cell death by cell proliferation assay; mitochondrial membrane potential and oxidative stress by flow cytometry after fluorescent staining of JC-1 and DHE, respectively. RESULTS: Leptin alone increased neuronal ATP supply, and was protective against MPP1-induced cell death, and associated with an increase in UCP2 expression. Leptin also significantly attenuated MPP1-induced ATP deficiency and mitochondrial depolarization. Stable knockdown of UCP2 expression reduced ATP levels, and completely abolished leptin protection against MPP1-induced cell death and ATP deficiency compared with vector controls. CONCLUSIONS: Leptin promotes neuronal survival by restoring MPP1-induced mitochondrial depolarization and ATP deficiency. Knockdown of UCP2 abolished leptin protection. Our results show that UCP2 is inducible and is critical in mediating the neuroprotective effects of leptin.