Proteomic alterations of distinct mitochondrial subpopulations in the type 1 diabetic heart: contribution of protein import dysfunction.
Diabetic cardiomyopathy is associated with increased risk of heart failure in type 1 diabetic patients. Mitochondrial dysfunction is suggested as an underlying contributor to diabetic cardiomyopathy. Cardiac mitochondria are characterized by subcellular spatial locale, including mitochondria located beneath the sarcolemma, subsarcolemmal mitochondria (SSM), and mitochondria situated between the myofibrils, interfibrillar mitochondria (IFM). The goal of this study was to determine whether type 1 diabetic insult in the heart influences proteomic make-up of spatially distinct mitochondrial subpopulations and to evaluate the role of nuclear encoded mitochondrial protein import. Utilizing multiple proteomic approaches (iTRAQ and two-dimensional-differential in-gel electrophoresis), IFM proteomic make-up was impacted by type 1 diabetes mellitus to a greater extent than SSM, as evidenced by decreased abundance of fatty acid oxidation and electron transport chain proteins. Mitochondrial phosphate carrier and adenine nucleotide translocator, as well as inner membrane translocases, were decreased in the diabetic IFM (P < 0.05 for both). Mitofilin, a protein involved in cristae morphology, was diminished in the diabetic IFM (P < 0.05). Posttranslational modifications, including oxidations and deamidations, were most prevalent in the diabetic IFM. Mitochondrial heat shock protein 70 (mtHsp70) was significantly decreased in diabetic IFM (P < 0.05). Mitochondrial protein import was decreased in the diabetic IFM with no change in the diabetic SSM (P < 0.05). Taken together, these results indicate that mitochondrial proteomic alterations in the type 1 diabetic heart are more pronounced in the IFM. Further, proteomic alterations are associated with nuclear encoded mitochondrial protein import dysfunction and loss of an essential mitochondrial protein import constituent, mtHsp70, implicating this process in the pathogenesis of the diabetic heart.
West Virginia University School of Medicine, Division of Exercise Physiology, Center for Cardiovascular and Respiratory Sciences, 1 Medical Center Dr., Morgantown, WV 26506, USA.
Walter A
WA
Baseler
Erinne R
ER
Dabkowski
Courtney L
CL
Williamson
Tara L
TL
Croston
Dharendra
D
Thapa
Matthew J
MJ
Powell
Trust T
TT
Razunguzwa
John M
JM
Hollander
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism; D000102:Acetyl-CoA C-Acyltransferase / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D019748:Carbon-Carbon Double Bond Isomerases / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002952:Citric Acid Cycle / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D058065:Diabetic Cardiomyopathies / Q000378:metabolism* / Q000503:physiopathology; D015536:Down-Regulation / Q000502:physiology; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004746:Enoyl-CoA Hydratase / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006321:Heart / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D008929:Mitochondria, Heart / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology; D021381:Protein Transport / Q000502:physiology*; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D019998:Racemases and Epimerases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D001786:Blood Glucose; D002352:Carrier Proteins; D045222:Electron Transport Chain Complex Proteins; D018840:HSP70 Heat-Shock Proteins; D007328:Insulin; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D020543:Proteome; D011993:Recombinant Fusion Proteins; C038784:fatty acid oxidation complex; C532603:mitofilin protein, mouse; D015094:3-Hydroxyacyl CoA Dehydrogenases; D000102:Acetyl-CoA C-Acyltransferase; D004746:Enoyl-CoA Hydratase; D019998:Racemases and Epimerases; D019748:Carbon-Carbon Double Bond Isomerases