Protein tyrosine nitration in the mitochondria from diabetic mouse heart. Implications to dysfunctional mitochondria in diabetes.
Oxidative stress has been implicated in dysfunctional mitochondria in diabetes. Tyrosine nitration of mitochondrial proteins was observed under conditions of oxidative stress. We hypothesize that nitration of mitochondrial proteins is a common mechanism by which oxidative stress causes dysfunctional mitochondria. The putative mechanism of nitration in a diabetic model of oxidative stress and functional changes of nitrated proteins were studied in this work. As a source of mitochondria, alloxan-susceptible and alloxan-resistant mice were used. These inbred strains are distinguished by the differential ability to detoxify free radicals. A proteomic approach revealed significant similarity between patterns of tyrosine-nitrated proteins generated in the heart mitochondria under different in vitro and in vivo conditions of oxidative stress. This observation points to a common nitrating species, which may derive from different nitrating pathways in vivo and may be responsible for the majority of nitrotyrosine formed. Functional studies show that protein nitration has an adverse effect on protein function and that protection against nitration protects functional properties of proteins. Because proteins that undergo nitration are involved in major mitochondrial functions, such as energy production, antioxidant defense, and apoptosis, we concluded that tyrosine nitration of mitochondrial proteins may lead to dysfunctional mitochondria in diabetes.
Turko
Illarion V
IV
Department of Integrative Biology and Pharmacology, Univeristy of Texas Medical School, Houston, 77030, USA.
Li
Li
L
Aulak
Kulwant S
KS
Stuehr
Dennis J
DJ
Chang
Jui-Yoa
JY
Murad
Ferid
F
D000496:Alloxan / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D002384:Catalysis; D003921:Diabetes Mellitus, Experimental; D015180:Electrophoresis, Gel, Two-Dimensional; D005609:Free Radicals; D005947:Glucose / Q000378:metabolism; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism*; D009584:Nitrogen / Q000737:chemistry / Q000378:metabolism*; D018384:Oxidative Stress; D011233:Precipitin Tests; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism*
D000975:Antioxidants; D005609:Free Radicals; D014443:Tyrosine; D000496:Alloxan; D005947:Glucose; D009584:Nitrogen