Natural Medicines Targeting Mitochondrial Dysfunction in Spinocerebellar Ataxia Type 3: A Narrative Review of Cellular and Molecular Events

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common autosomal dominant spinocerebellar ataxia and is characterized by progressive neurodegeneration for which no Food and Drug Administration (FDA)-approved therapeutics are currently available. Mitochondrial dysfunction has emerged as a central pathogenic mechanism in SCA3, making it a promising therapeutic target. This narrative review aims to evaluate the published evidence on the therapeutic potential of natural medicines and their active compounds targeting mitochondrial dysfunction in SCA3. This review summarizes published evidence on the therapeutic potential of natural medicines and their active compounds targeting mitochondrial dysfunction in SCA3 in preclinical studies. The reviewed studies suggest the therapeutic potential of Glycyrrhiza inflata, Codonopsis pilosula, Ginkgo biloba, Poria cocos, Pueraria lobata, Rehmannia glutinosa, Curcuma longa, Hericium erinaceus, Astragalus membranaceus, Hemerocallis citrina, caffeic acid, and resveratrol in targeting mitochondrial dysfunction in SCA3. These natural medicines were reported to regulate multiple mitochondrial-associated pathways, including oxidative stress, mitochondrial membrane potential, mitochondrial bioenergetics, mitochondrial dynamics, mitochondrial quality control, and mitochondria-mediated apoptosis, thereby improving neuronal survival and mitochondrial function in experimental SCA3 models. In conclusion, natural medicines targeting mitochondrial dysfunction represent promising preclinical candidates for further investigation in SCA3. However, further mechanistic investigations, well-designed clinical trials, and optimization of pharmacokinetic properties are required to facilitate their translation into clinical practice.