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Role of the ubiquitin-proteasome system in cardiac dysfunction of adipose triglyceride lipase-deficient mice.

Mussbacher M, Stessel H, Wölkart G, Haemmerle G, Zechner R, Mayer B, Schrammel A - J. Mol. Cell. Cardiol. (2014)

Bottom Line: Dysfunction of the UPS was accompanied by activation of NF-κB signaling.Chronic treatment of ATGL-deficient mice with the PPARα agonist Wy14,643 improved proteasomal function, prevented NF-κB activation and decreased oxidative stress.In summary, our data point to a hitherto unrecognized link between proteasomal function, PPARα signaling and cardiovascular disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, A-8010 Graz, Austria. Electronic address: marion.mussbacher@uni-graz.at.

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Interplay of signaling pathways leading to cardiac dysfunction. ATGL deficiency in cardiomyocytes results in decreased production of lipid ligands for PPARα activation. Consequent mitochondrial dysfunction results in decreased intracellular ATP levels, leading to reduced activation of the 26S proteasome (path 1). Proteasomal dysfunction causes accumulation and aggregation of ubiquitinated proteins. Increased oxidative inflammatory stress may damage critical residues/domains within the catalytic core of the proteasome (path 2). Damaged and/or misfolded proteins impair proteasomal activity by saturation of the 20S core with non-degradable aggregates (path 3). Restored PPARα signaling with Wy14,643 reduces oxidative inflammatory stress, improves mitochondrial function, and consequently increases UPS activity and cardiac performance.
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sch0005: Interplay of signaling pathways leading to cardiac dysfunction. ATGL deficiency in cardiomyocytes results in decreased production of lipid ligands for PPARα activation. Consequent mitochondrial dysfunction results in decreased intracellular ATP levels, leading to reduced activation of the 26S proteasome (path 1). Proteasomal dysfunction causes accumulation and aggregation of ubiquitinated proteins. Increased oxidative inflammatory stress may damage critical residues/domains within the catalytic core of the proteasome (path 2). Damaged and/or misfolded proteins impair proteasomal activity by saturation of the 20S core with non-degradable aggregates (path 3). Restored PPARα signaling with Wy14,643 reduces oxidative inflammatory stress, improves mitochondrial function, and consequently increases UPS activity and cardiac performance.

Mentions: Our current working hypothesis is depicted in Scheme 1. ATGL deficiency in cardiomyocytes results in massively reduced triacylglyceride hydrolysis and consequently decreased production of lipid ligands for PPARα activation (e.g. fatty acids, acyl-CoA and various fatty acid-derived compounds) [9]. As PPARα signaling is an important key player in energy metabolism and inflammation, its downregulation leads to deleterious consequences such as disrupted mitochondrial substrate oxidation and consequent decreased ATP production. Since ATP is required for 19S-mediated channel opening and substrate unfolding, limited ATP availability causes decreased activation of the 26S proteasome (path 1). Proteasomal dysfunction entails insufficient degradation of target proteins, thus resulting in accumulation and aggregation of ubiquitinated products. In a circulus vitiosus, these aggregates further inhibit proteasomal activities, which causes additional cellular stress [29]. Considering the presence of oxidative inflammatory stress in AKO animals, disturbances of the cardiac UPS might also originate from oxidative modifications of critical residues within the catalytic core of the proteasome (path 2). Recent studies have shown that distinct subunits are susceptible to oxidative modifications, including carbonylation, hydroxynonenal-mediated alkylation, and S-glutathionylation [23,30–32]. In addition, enhanced superoxide production may also cause protein crosslinking through formation of Schiff bases and/or disulfide bridges [33] which might lead to saturation of the proteasome by non-degradable aggregates (path 3). Defective proteasomal activity together with mitochondrial dysfunction is implicated in the development of cardiac dysfunction and premature death of AKO animals. Pharmacological intervention with the PPARα agonist Wy14,643 improves mitochondrial and proteasomal functions as well as oxidative and inflammatory stress.


Role of the ubiquitin-proteasome system in cardiac dysfunction of adipose triglyceride lipase-deficient mice.

Mussbacher M, Stessel H, Wölkart G, Haemmerle G, Zechner R, Mayer B, Schrammel A - J. Mol. Cell. Cardiol. (2014)

Interplay of signaling pathways leading to cardiac dysfunction. ATGL deficiency in cardiomyocytes results in decreased production of lipid ligands for PPARα activation. Consequent mitochondrial dysfunction results in decreased intracellular ATP levels, leading to reduced activation of the 26S proteasome (path 1). Proteasomal dysfunction causes accumulation and aggregation of ubiquitinated proteins. Increased oxidative inflammatory stress may damage critical residues/domains within the catalytic core of the proteasome (path 2). Damaged and/or misfolded proteins impair proteasomal activity by saturation of the 20S core with non-degradable aggregates (path 3). Restored PPARα signaling with Wy14,643 reduces oxidative inflammatory stress, improves mitochondrial function, and consequently increases UPS activity and cardiac performance.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263609&req=5

sch0005: Interplay of signaling pathways leading to cardiac dysfunction. ATGL deficiency in cardiomyocytes results in decreased production of lipid ligands for PPARα activation. Consequent mitochondrial dysfunction results in decreased intracellular ATP levels, leading to reduced activation of the 26S proteasome (path 1). Proteasomal dysfunction causes accumulation and aggregation of ubiquitinated proteins. Increased oxidative inflammatory stress may damage critical residues/domains within the catalytic core of the proteasome (path 2). Damaged and/or misfolded proteins impair proteasomal activity by saturation of the 20S core with non-degradable aggregates (path 3). Restored PPARα signaling with Wy14,643 reduces oxidative inflammatory stress, improves mitochondrial function, and consequently increases UPS activity and cardiac performance.
Mentions: Our current working hypothesis is depicted in Scheme 1. ATGL deficiency in cardiomyocytes results in massively reduced triacylglyceride hydrolysis and consequently decreased production of lipid ligands for PPARα activation (e.g. fatty acids, acyl-CoA and various fatty acid-derived compounds) [9]. As PPARα signaling is an important key player in energy metabolism and inflammation, its downregulation leads to deleterious consequences such as disrupted mitochondrial substrate oxidation and consequent decreased ATP production. Since ATP is required for 19S-mediated channel opening and substrate unfolding, limited ATP availability causes decreased activation of the 26S proteasome (path 1). Proteasomal dysfunction entails insufficient degradation of target proteins, thus resulting in accumulation and aggregation of ubiquitinated products. In a circulus vitiosus, these aggregates further inhibit proteasomal activities, which causes additional cellular stress [29]. Considering the presence of oxidative inflammatory stress in AKO animals, disturbances of the cardiac UPS might also originate from oxidative modifications of critical residues within the catalytic core of the proteasome (path 2). Recent studies have shown that distinct subunits are susceptible to oxidative modifications, including carbonylation, hydroxynonenal-mediated alkylation, and S-glutathionylation [23,30–32]. In addition, enhanced superoxide production may also cause protein crosslinking through formation of Schiff bases and/or disulfide bridges [33] which might lead to saturation of the proteasome by non-degradable aggregates (path 3). Defective proteasomal activity together with mitochondrial dysfunction is implicated in the development of cardiac dysfunction and premature death of AKO animals. Pharmacological intervention with the PPARα agonist Wy14,643 improves mitochondrial and proteasomal functions as well as oxidative and inflammatory stress.

Bottom Line: Dysfunction of the UPS was accompanied by activation of NF-κB signaling.Chronic treatment of ATGL-deficient mice with the PPARα agonist Wy14,643 improved proteasomal function, prevented NF-κB activation and decreased oxidative stress.In summary, our data point to a hitherto unrecognized link between proteasomal function, PPARα signaling and cardiovascular disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of Graz, Universitätsplatz 2, A-8010 Graz, Austria. Electronic address: marion.mussbacher@uni-graz.at.

Show MeSH
Related in: MedlinePlus