Metabolic derangement in polycystic kidney disease mouse models is ameliorated by mitochondrial-targeted antioxidants
| Autor: | Dao-Fu Dai, Yi Chu, Gloria A. Benavides, Michelle S. Johnson, Kung-Sik Chan, Victor M. Darley-Usmar, Fei Wu, Nastaran Daneshgar, Peir-In Liang, Michael Kinter, Andrew W. Baguley, Jianhua Zhang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Mitochondrial ROS
QH301-705.5 Autosomal dominant polycystic kidney disease Medicine (miscellaneous) Mitochondrion medicine.disease_cause urologic and male genital diseases General Biochemistry Genetics and Molecular Biology Article Antioxidants Cell Line Polycystic kidney disease medicine Animals Humans Biology (General) Beta oxidation PKD1 Chemistry urogenital system Energy metabolism medicine.disease Polycystic Kidney Autosomal Dominant female genital diseases and pregnancy complications Cell biology Mitochondria Citric acid cycle Disease Models Animal General Agricultural and Biological Sciences Oxidative stress |
| Zdroj: | Communications Biology Communications Biology, Vol 4, Iss 1, Pp 1-13 (2021) |
| ISSN: | 2399-3642 |
| Popis: | 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. Daneshgar et al. investigated the role of mitochondrial dysfunction in ADPKD and mitochondria protective agents as potential therapeutics. The authors reported decreased mitochondrial complex activity and downregulation of mitochondrial and metabolic proteins in ADPKD, and proposed mCAT overexpression or SS31 treatment to slow cystogenesis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink