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Metabolic derangement in polycystic kidney disease mouse models is ameliorated by mitochondrial-targeted antioxidants
Nastaran Daneshgar1, Andrew W Baguley1, Peir-In Liang1,2
1Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Abstract:
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressively enlarging cysts. Here we elucidate the interplay between oxidative stress, mitochondrial dysfunction, and metabolic derangement using two mouse models of PKD1 mutation, PKD1RC/null and PKD1RC/RC. Mouse kidneys with PKD1 mutation have decreased mitochondrial complexes activity. Targeted proteomics analysis shows a significant decrease in proteins involved in the TCA cycle, fatty acid oxidation (FAO), respiratory complexes, and endogenous antioxidants. Overexpressing mitochondrial-targeted catalase (mCAT) using adeno-associated virus reduces mitochondrial ROS, oxidative damage, ameliorates the progression of PKD and partially restores expression of proteins involved in FAO and the TCA cycle. In human ADPKD cells, inducing mitochondrial ROS increased ERK1/2 phosphorylation and decreased AMPK phosphorylation, whereas the converse was observed with increased scavenging of ROS in the mitochondria. Treatment with the mitochondrial protective peptide, SS31, recapitulates the beneficial effects of mCAT, supporting its potential application as a novel therapeutic for ADPKD.
Insights
Mitochondrial dysfunction drives Autosomal dominant polycystic kidney disease (ADPKD) progression. Restoring mitochondrial health via antioxidants or protective peptides ameliorates cyst growth and metabolic issues in ADPKD models.
Area of Science:
- Nephrology
- Mitochondrial Biology
- Molecular Medicine
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder marked by kidney cyst development.
- Oxidative stress and mitochondrial dysfunction are implicated in ADPKD pathogenesis but their interplay with metabolism remains unclear.
Purpose of the Study:
- To investigate the relationship between oxidative stress, mitochondrial dysfunction, and metabolic changes in ADPKD.
- To evaluate the therapeutic potential of targeting mitochondrial dysfunction in ADPKD.
Main Methods:
- Utilized two mouse models (PKD1RC/null and PKD1RC/RC) of ADPKD.
- Performed targeted proteomics to analyze protein expression in kidney tissues.
- Employed adeno-associated virus (AAV) to overexpress mitochondrial-targeted catalase (mCAT) in vivo.
- Investigated cellular responses in human ADPKD cells and treated with SS31 peptide.
Main Results:
- PKD1-mutated kidneys exhibited reduced mitochondrial complex activity, impaired fatty acid oxidation (FAO), and decreased antioxidant levels.
- Overexpression of mCAT in mouse models reduced mitochondrial reactive oxygen species (ROS), oxidative damage, and slowed PKD progression.
- mCAT treatment partially restored FAO and TCA cycle protein expression; SS31 peptide showed similar protective effects in human ADPKD cells.
Conclusions:
- Mitochondrial dysfunction, oxidative stress, and metabolic derangements are key interconnected factors in ADPKD.
- Targeting mitochondrial ROS with agents like mCAT or SS31 peptide shows therapeutic promise for ADPKD.
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