Impacts of Metabolic and Mitochondrial Reprogramming on ADPKD Drug Targets and Repurposing

Autosomal dominant polycystic kidney disease (ADPKD) is a complex disorder characterized by the progressive development of renal cysts and systemic complications, including cardiovascular and metabolic comorbidities. Disease progression is linked to ADPKD-driven metabolic and mitochondrial reprogramming that exacerbates ADPKD pathophysiology by impairing central energetic pathways, including mitochondrial respiration and glucose, lipid, and amino acid metabolism. Recent studies have revealed that caloric intake interventions can attenuate disease progression; however, they are difficult to achieve and likely applicable only to those who are overweight. Therefore, a better understanding of the mechanisms that drive metabolic and mitochondrial reprogramming may foster the identification of novel ADPKD severity-modifying drug targets and/or drugs. Such drugs could synergistically complement the benefits of tolvaptan (the only US Food and Drug Administration (FDA)-approved ADPKD therapeutic), or serve as alternatives to it, as tolvaptan is costly and associated with idiosyncratic hepatotoxicity. Repurposing FDA-approved drugs could accelerate clinical testing and subsequent translation to practice by building on prior work to improve the traditional drug development pipeline. To facilitate identification of repurposed drugs for ADPKD, we review ADPKD-driven metabolic and mitochondrial reprogramming from the perspective of drug target identification for repurposing ADPKD therapeutics.