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  • Review Article
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Metabolism and mitochondria in polycystic kidney disease research and therapy

Nature Reviews Nephrology volume 14, pages 678–687 (2018)Cite this article

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Abstract

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.

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 morphology.

  • The energy sensor AMP-activated protein kinase (AMPK) regulates at least two key processes that are altered in ADPKD, mechanistic target of rapamycin complex 1 (mTORC1) signalling and the activity of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel.

  • Targeting the metabolic alterations in ADPKD ameliorates cyst progression in rodent and non-rodent models of ADPKD, and thus, these alterations might be novel therapeutic targets.

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Fig. 1: Signalling pathways that are regulated by polycystin proteins.
Fig. 2: Polycystin proteins positively regulate mitochondrial function by several mechanisms.
Fig. 3: Therapeutic targets in metabolic pathways that are affected in ADPKD.

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Acknowledgements

The authors thank their colleagues in their laboratories for very helpful and thought-provoking discussions. Relevant work from the authors’ laboratories was supported by the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant R01DK072614 (M.J.C.), US Department of Defense (DoD) grant W81XWH-15-1-0419 (M.J.C.), the Italian Ministry of Health grant RF11-12 (A.B.), the PKD Foundation grant 187G14a/b (A.B.) and the Italian Association for PKD (AIRP) (A.B.).

Reviewer information

Nature Reviews Nephrology thanks J. Calvet, V. Torres and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA

    Valeria Padovano & Michael J. Caplan

  2. Division of Genetics and Cell Biology, Dibit, San Raffaele Scientific Institute, Milan, Italy

    Christine Podrini & Alessandra Boletta

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Glossary

Warburg effect

The use of glycolysis as the major cellular energy source without using oxygen, even when it is available, resulting in lactate production. First reported in cancer cells but also observed in other hyperproliferative cell types.

Oxidative phosphorylation

(OXPHOS). The production of ATP from ADP using the electrochemical gradient created through the activity of the electron transport chain of the inner membrane of mitochondrion.

Fatty acid β-oxidation

(FAO). The production of energy by the catabolism of fatty acids.

Han:SPRD rat

A non-orthologous rat model of chronic, progressive renal cystic disease that is caused by a missense mutation in ankyrin repeat and sterile α-motif domain-containing 6 (Anks6; also known as Pkdr1).

Network node

A central hub where different gene expression networks interconnect.

Maturity onset diabetes of the young, type 1

(MODY1). An autosomal dominant condition, usually with an early adult onset and characterized by features of metabolic syndrome.

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Padovano, V., Podrini, C., Boletta, A. et al. Metabolism and mitochondria in polycystic kidney disease research and therapy. Nat Rev Nephrol 14, 678–687 (2018). https://doi.org/10.1038/s41581-018-0051-1

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