TY - JOUR
T1 - Metabolic reprogramming and the role of mitochondria in polycystic kidney disease
AU - Podrini, Christine
AU - Cassina, Laura
AU - Boletta, Alessandra
N1 - Funding Information:
The authors are grateful to other members of the lab Boletta for helpful suggestions. The work on metabolism and mitochondria was funded by The PKD Foundation ( RFA187G14 and RFA218G18 to AB) and by the Italian Ministry of Health ( RF-2011-02351840 to AB and GR-2016-02364851 to CP).
Publisher Copyright:
© 2019 The Authors
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/3
Y1 - 2020/3
N2 - Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a slowly progressive disease characterized by the relentless growth of renal cysts throughout the life of affected individuals. Early evidence suggested that the epithelia lining the cysts share neoplastic features, leading to the definition of PKD as a “neoplasm in disguise”. Recent work from our and other laboratories has identified a profound metabolic reprogramming in PKD, similar to the one reported in cancer and consistent with the reported increased proliferation. Multiple lines of evidence suggest that aerobic glycolysis (a Warburg-like effect) is present in the disease, along with other metabolic dysfunctions such as an increase in the pentose phosphate pathway, in glutamine anaplerosis and fatty acid biosynthesis, while fatty acid oxidation and oxidative phosphorylation (OXPHOS) are decreased. In addition to glutamine, other amino acid-related pathways appear altered, including asparagine and arginine. The precise origin of the metabolic alterations is not entirely clear, but two hypotheses can be formulated, not mutually exclusive. First, the polycystins have been recently shown to regulate directly mitochondrial function and structure either by regulating Ca2+ uptake in mitochondria at the Mitochondria Associated Membranes (MAMs) of the Endoplasmic Reticulum, or by a direct translocation of a small fragment of the protein into the matrix of mitochondria. One alternative possibility is that metabolic and mitochondrial dysfunctions in ADPKD are secondary to the de-regulation of proliferation, driven by the multiple signaling pathways identified in the disease, which include mTORC1 and AMPK among the most relevant. While the precise mechanisms underlying these novel alterations identified in ADPKD will need further investigation, it is evident that they offer a great opportunity for novel interventions in the disease.
AB - Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a slowly progressive disease characterized by the relentless growth of renal cysts throughout the life of affected individuals. Early evidence suggested that the epithelia lining the cysts share neoplastic features, leading to the definition of PKD as a “neoplasm in disguise”. Recent work from our and other laboratories has identified a profound metabolic reprogramming in PKD, similar to the one reported in cancer and consistent with the reported increased proliferation. Multiple lines of evidence suggest that aerobic glycolysis (a Warburg-like effect) is present in the disease, along with other metabolic dysfunctions such as an increase in the pentose phosphate pathway, in glutamine anaplerosis and fatty acid biosynthesis, while fatty acid oxidation and oxidative phosphorylation (OXPHOS) are decreased. In addition to glutamine, other amino acid-related pathways appear altered, including asparagine and arginine. The precise origin of the metabolic alterations is not entirely clear, but two hypotheses can be formulated, not mutually exclusive. First, the polycystins have been recently shown to regulate directly mitochondrial function and structure either by regulating Ca2+ uptake in mitochondria at the Mitochondria Associated Membranes (MAMs) of the Endoplasmic Reticulum, or by a direct translocation of a small fragment of the protein into the matrix of mitochondria. One alternative possibility is that metabolic and mitochondrial dysfunctions in ADPKD are secondary to the de-regulation of proliferation, driven by the multiple signaling pathways identified in the disease, which include mTORC1 and AMPK among the most relevant. While the precise mechanisms underlying these novel alterations identified in ADPKD will need further investigation, it is evident that they offer a great opportunity for novel interventions in the disease.
KW - Cell Signaling
KW - Glucose
KW - Lipids
KW - Metabolism
KW - Mitochondria
KW - OXPHOS
KW - Polycystic kidney disease
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U2 - 10.1016/j.cellsig.2019.109495
DO - 10.1016/j.cellsig.2019.109495
M3 - Article
C2 - 31816397
AN - SCOPUS:85076342523
VL - 67
JO - Cellular Signalling
JF - Cellular Signalling
SN - 0898-6568
M1 - 109495
ER -