Metabolism and mitochondria in polycystic kidney disease research and therapy

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common, potentially lethal, monogenic diseases and is caused predominantly by mutations in polycystic kidney disease 1 ( PKD1 ) and PKD2 , which encode polycystin 1 (PC1) and PC2, respectively. Over the decades-long course of the disease, patients develop large fluid-filled renal cysts that impair kidney function, leading to end-stage renal disease in ~50% of patients. Despite the identification of numerous dysregulated pathways in ADPKD, the molecular mechanisms underlying the renal dysfunction from mutations in PKD genes and the physiological functions of the polycystin proteins are still unclear. Alterations in cell metabolism have emerged in the past decade as a hallmark of ADPKD. ADPKD cells shift their mode of energy production from oxidative phosphorylation to alternative pathways, such as glycolysis. In addition, the polycystins seem to play regulatory roles in modulating mechanisms and machinery related to energy production and utilization, including AMPK, PPARα, PGC1α, calcium signalling at mitochondria-associated membranes, mTORC1, cAMP and CFTR-mediated ion transport as well as the expression of crucial components of the mitochondrial energy production apparatus. In this Review, we explore these metabolic changes and discuss in detail the relationship between energy metabolism and ADPKD pathogenesis and identify potential therapeutic targets. In this Review, Caplan and colleagues describe the metabolic alterations in autosomal dominant polycystic kidney disease and how these might be novel therapeutic targets in the treatment of polycystic kidney disease. Key points Metabolic reprogramming has emerged as an important aspect of the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). Increased glycolysis, defective fatty acid β-oxidation and altered mitochondrial function have been observed both in vitro and in vivo in animal models of ADPKD and in tissues from patients with ADPKD. Polycystin proteins can directly regulate mitochondrial function; for example, the polycystin 1 (PC1)–PC2 complex at mitochondria-associated membranes can directly regulate oxidative phosphorylation by mediating mitochondrial calcium uptake. Polycystin proteins can indirectly affect mitochondrial function through regulation of calcium signalling, reduction of cAMP levels, inhibition of miR-17, maintenance of mitochondrial DNA (mtDNA) copy number and modulation of mitochondrial mor