title: The ubiquitin-proteasome system and autophagy are defective in the taurine-deficient heart.
abstract: Taurine depletion leads to impaired mitochondrial function, as characterized by reduced ATP production and elevated superoxide generation. These defects can fundamentally alter cardiomyocyte function and if left unchanged can result in cell death. To protect against these stresses, cardiomyocytes possess quality control processes, such as the ubiquitin-proteasome system (UPS) and autophagy, which can rejuvenate cells through the degradation of damaged proteins and organelles. Hence, the present study tested the hypothesis that reactive oxygen species generated by damaged mitochondria initiates UPS and autophagy in the taurine-deficient heart. Using transgenic mice lacking the taurine transporter (TauTKO) as a model of taurine deficiency, it was shown that the levels of ubiquitinated protein were elevated, an effect associated with a decrease in ATP-dependent 26S β5 proteasome activity. Treating the TauTKO mouse with the mitochondria-specific antioxidant, mitoTEMPO, largely abolished the increase in ubiquitinated protein content. The TauTKO heart was also associated with impaired autophagy, characterized by an increase in the initiator, Beclin-1, and autophagosome content, but a defect in the generation of active autophagolysosomes. Although mitoTEMPO treatment only restores the oxidative balance within the mitochondria, it appeared to completely disrupt the crosstalk between the damaged mitochondria and the quality control processes. Thus, mitochondrial oxidative stress is the main trigger initiating the quality control systems in the taurine-deficient heart. We conclude that the activation of the UPS and autophagy is another fundamental function of mitochondria.
authors.affiliation: Department of Pharmacology, University of South Alabama College of Medicine, Mobile, AL, 36688, USA.
authors.forename: Chian Ju
authors.initials: CJ
authors.lastname: Jong
authors.affiliation: School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ito
authors.affiliation: Department of Pharmacology, University of South Alabama College of Medicine, Mobile, AL, 36688, USA. sschaffe@southalabama.edu.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Schaffer
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy; D006321:Heart / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology; D009943:Organophosphorus Compounds / Q000737:chemistry; D018384:Oxidative Stress; D010588:Phagosomes / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011786:Quality Control; D051381:Rats; D017208:Rats, Wistar; D013654:Taurine / Q000172:deficiency / Q000502:physiology*; D054875:Ubiquitination; D000099247:Taurine Transporters
chemical_list: D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009943:Organophosphorus Compounds; D010880:Piperidines; D046988:Proteasome Endopeptidase Complex; D013654:Taurine; D000099247:Taurine Transporters; C555916:MitoTEMPO; C061553:ATP dependent 26S protease
keywords: Autophagosome formation; Consequences of mitochondrial oxidative stress; Defective autophagolysosome; Mitochondrial morphology; Proteasome activity; Protein degradation; Taurine deficiency