The gut-brain-mitophagy axis: Urolithin A as a transcriptional activator of Parkin in Alzheimer's and Parkinson's diseases.

Mitochondrial dysfunction is a cardinal, causative, and convergent hallmark in both Alzheimer's disease (AD) and Parkinson's disease (PD). However, therapeutics that target the process of mitophagy, the selective removal of damaged mitochondria, are relatively undeveloped. Prior work has largely centered around post-translational modifications of the PINK1-Parkin signaling pathway while ignoring the key need for sustained protein synthesis of Parkin. In this review, we explore an innovative transcriptional circuit involving the gut microbiome, AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and mitophagy: gut-derived metabolites, such as Urolithin A (UA), activate AMPK and SIRT1, both of which converge to deacetylate and phosphorylate peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The transcription of the mitophagy protein, Parkin, is then driven by activation of PGC-1α. This UA/AMPK/SIRT1/PGC-1α/Parkin/mitophagy pathway is disrupted in multiple layers in AD and PD; this includes impaired gut function, lowering the level of UA produced in the body, proteinopathy leading to reduced PGC-1α activity, and decreased transcription of Parkin. Therapeutic targets of these various nodes include UA, PGC-1α activator ZLN005, and SIRT1 activators, such as resveratrol or nicotinamide riboside. By shifting the paradigm from post-translational activation to transcriptional restoration of Parkin, this gut-brain metabolic axis offers a unifying, testable, and therapeutically tractable framework for mitigating mitophagy failure in AD and PD.