TY - JOUR
T1 - Increased mitochondrial fragmentation in polycystic kidney disease acts as a modifier of disease progression
AU - Cassina, Laura
AU - Chiaravalli, Marco
AU - Boletta, Alessandra
N1 - Funding Information:
The authors are grateful to other members of the Boletta laboratory for helpful discussions and particularly to Dr. Roberto Pagliarini for help with the graphs and statistical analysis. This research was funded by the PKD Foundation US (PKD-218G18A), the Italian Association for Research on PKD (AIRP). The authors are grateful to Dr. S. Bramani for her continuous support. Technical help was provided by: the Advanced Light and Electron Microscopy BioImaging Center (ALEMBIC), established by the San Raffaele Scientific Institute and the Vita-Salute San Raffaele University, for imaging analyses, in particular C. Panzeri for TEM imaging and V. Berno for fluorescence imaging; the Ospedale San Raffaele Mouse Clinic Intramural Project for technical support, in particular A. Fiocchi for histologic analysis and M. Raso from the Clinical Chemistry and Hematology Murine Laboratory for hematologic analyses.
Publisher Copyright:
© 2020 IRCCS Ospedale San Raffaele. The FASEB Journal published by Wiley Periodicals, Inc. on behalf of Federation of American Societies for Experimental Biology
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic disorder, characterized by bilateral renal cyst formation. Multiple pathways are de-regulated in cystic epithelia offering good opportunities for therapy. Others and we have previously reported that metabolic reprogramming, including alterations of the TCA cycle, are prominent features of ADPKD. Several lines of evidence suggest that mitochondrial impairment might be responsible for the metabolic alterations. Here, we performed morphologic and morphometric evaluation of mitochondria by TEM in an orthologous mouse model of PKD caused by mutations in the Pkd1 gene (Ksp-Cre;Pkd1flox/−). Furthermore, we measured mitochondrial respiration by COX and SDH enzymatic activity in situ. We found several alterations including reduced mitochondrial mass, altered structure and fragmentation of the mitochondrial network in cystic epithelia of Ksp-Cre;Pkd1flox/− mice. At the molecular level, we found reduced expression of the pro-fusion proteins OPA1 and MFN1 and up-regulation of the pro-fission protein DRP1. Importantly, administration of Mdivi-1, which interferes with DRP1 rescuing mitochondrial fragmentation, significantly reduced kidney/body weight, cyst formation, and improved renal function in Ksp-Cre;Pkd1flox/− mice. Our data indicate that impaired mitochondrial structure and function play a role in disease progression, and that their improvement can significantly modify the course of the disease.
AB - Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic disorder, characterized by bilateral renal cyst formation. Multiple pathways are de-regulated in cystic epithelia offering good opportunities for therapy. Others and we have previously reported that metabolic reprogramming, including alterations of the TCA cycle, are prominent features of ADPKD. Several lines of evidence suggest that mitochondrial impairment might be responsible for the metabolic alterations. Here, we performed morphologic and morphometric evaluation of mitochondria by TEM in an orthologous mouse model of PKD caused by mutations in the Pkd1 gene (Ksp-Cre;Pkd1flox/−). Furthermore, we measured mitochondrial respiration by COX and SDH enzymatic activity in situ. We found several alterations including reduced mitochondrial mass, altered structure and fragmentation of the mitochondrial network in cystic epithelia of Ksp-Cre;Pkd1flox/− mice. At the molecular level, we found reduced expression of the pro-fusion proteins OPA1 and MFN1 and up-regulation of the pro-fission protein DRP1. Importantly, administration of Mdivi-1, which interferes with DRP1 rescuing mitochondrial fragmentation, significantly reduced kidney/body weight, cyst formation, and improved renal function in Ksp-Cre;Pkd1flox/− mice. Our data indicate that impaired mitochondrial structure and function play a role in disease progression, and that their improvement can significantly modify the course of the disease.
KW - cellular respiration
KW - Mdivi-1
KW - mitochondrial fragmentation
KW - polycystic kidney disease
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U2 - 10.1096/fj.201901739RR
DO - 10.1096/fj.201901739RR
M3 - Article
C2 - 32239723
AN - SCOPUS:85082841755
VL - 34
SP - 6493
EP - 6507
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 5
ER -