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Increased mitochondrial fragmentation in polycystic kidney disease acts as a modifier of disease progression
- Source :
- The FASEB Journal. 34:6493-6507
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
Cellular respiration
Autosomal dominant polycystic kidney disease
Mitochondrion
Biology
Biochemistry
Mice
03 medical and health sciences
0302 clinical medicine
Internal medicine
Genetics
medicine
Polycystic kidney disease
Animals
MFN1
Fragmentation (cell biology)
Molecular Biology
Cell Proliferation
Mice, Knockout
Polycystic Kidney Diseases
Kidney
PKD1
Cysts
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
medicine.disease
Mitochondria
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
Endocrinology
medicine.anatomical_structure
Disease Progression
030217 neurology & neurosurgery
Biotechnology
Subjects
Details
- ISSN :
- 15306860 and 08926638
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- The FASEB Journal
- Accession number :
- edsair.doi.dedup.....66af908f2238438202d3bc492757747f