Costunolide Ameliorates the Methylmalonic Acidemia Via the PINK1/Parkin Pathway

Abstract

Methylmalonic acidemia (MMA) is a congenital organic acidemia characterized by mitochondrial dysfunction due to the abnormal accumulation of intermediate metabolites, which subsequently leads to brain damage. Currently, there are no specific pharmacological treatments available for MMA in clinical practice. Costunolide (COS) is a sesquiterpenoid compound derived from Radix Aucklandiae, it exhibits a broad spectrum of bioactivities. However, its effects on MMA have not yet been evaluated. For in-vivo studies, the MMA rat model was established by subcutaneous injection of methylmalonic acid (MA). The spatial learning memory flexibility observed by Morris water maze and brain damage were restored in MMA rats after COS treatment. JC-1 detection and measurements of oxidative stress indicators were performed to demonstrate that the abnormal mitochondrial membrane potential (MMP) and oxidative stress levels were recovered in hippocampus of MMA rats after COS (20 mg/kg) treatment. The abnormal expression of autophagy-related proteins induced by MMA was also rectified following COS treatment. In-vitro research utilized PC12 cells to further investigate the underlying mechanisms of COS in regulating MMA. Our results indicated that COS (20µM) ameliorated the oxidative stress level and mitophagy. Pink1 knockdown reversed the apoptosis rate and MMP which were improved by COS (20µM). Concurrently, the beneficial effects of COS on ATP concentration, ROS level and autophagy related protein expression level were also offset by PINK1 knockdown. In conclusion, our study confirms that COS promotes mitochondrial autophagy and mitigates oxidative stress via the PINK1/Parkin pathway, thereby improving cognitive impairments associated with MMA.