Enhanced apoptotic propensity in diabetic cardiac mitochondria: influence of subcellular spatial location

Williamson, Courtney L.; Dabkowski, Erinne R.; Baseler, Walter A.; Croston, Tara L.; Alway, Stephen E.; Hollander, John M.

doi:10.1152/ajpheart.00668.2009

Cited by 85 publications

(113 citation statements)

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“…It was reported that mitochondria from STZ-induced diabetic mouse hearts display a decreased state 3 respiration ( 34-36 ) and an increased propensity for mPTP opening in response to oxidative stress ( 39 ). Figure 10 shows the decreased glutamate/malate supported state 3 respiration both in SSM (by 26%) and IFM (by 25%), while state 4 has not been affected.…”

Section: Knocking Down Ncdase Exacerbates Mitochondrial Dysfunction Imentioning

confidence: 90%

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Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Novgorodov

Riley

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.orgCompelling epidemiological and clinical data indicate that diabetes mellitus increases the risk for cardiac dysfunction and heart failure independently of other risk factors, such as coronary disease and hypertension. Lipotoxicity is an important contributor to cardiac dysfunction in both type 1 ( 1, 2 ) and type 2 ( 3-6 ) diabetes, which are characterized by excessive accumulation of triacylglycerols, long-chain acyl-CoAs, diacylglycerols, and ceramides in myocardium. Correlation of the increased ceramide level with development of diabetic cardiomyopathy has attracted special attention in recent years because of the well-documented ability of this sphingolipid to regulate a number of cell processes, including cell proliferation, growth arrest, differentiation and apoptosis, and the mediation of responses to stress stimuli .Ceramide is a hub of sphingolipid metabolism ( 7,8 ). The balance between ceramide-producing pathways and pathways that consume it dictates ceramide level in the cell. The de novo ceramide biosynthesis pathway, one of the major ceramide producing pathways, localizes in the endoplasmic reticulum (ER) and starts with the condensation of serine and palmitoyl-CoA producing 3-ketosphingonine, which, in turn, is rapidly converted to dihydrosphingosine. Subsequent acylation of dihydrosphingosine by a set of (dihydro)ceramide synthases (CerSs) gives rise to dihydroceramide. Finally, the removal of two hydrogens from the fatty acid chain of dihydroceramide by desaturase leads to the formation of ceramide. Other possible contributors to elevated ceramide level are: hydrolysis of SM catalyzed by SMases, Abstract Sphingolipids have been implicated as key mediators of cell-stress responses and effectors of mitochondrial function. To investigate potential mechanisms underlying mitochondrial dysfunction, an important contributor to diabetic cardiomyopathy, we examined alterations of cardiac sphingolipid metabolism in a mouse with streptozotocininduced type 1 diabetes. Diabetes increased expression of desaturase 1, (dihydro)ceramide synthase (CerS)2, serine palmitoyl transferase 1, and the rate of ceramide formation by mitochondria-resident CerSs, indicating an activation of ceramide biosynthesis. However, the lack of an increase in mitochondrial ceramide suggests concomitant upregulation of ceramide-metabolizing pathways. Elevated levels of lactosylceramide, one of the initial products in the formation of glycosphingolipids were accompanied with decreased respiration and calcium retention capacity (CRC) in mitochondria from diabetic heart tissue. In baseline mitochondria, lactosylceramide potently suppressed state 3 respiration and decreased CRC, suggesting lactosylceramide as the primary sphingolipid responsible for mitochondrial defects in diabetic hearts. Moreover, knocking down the neutral ceramidase (NCDase) resulted in an increase in lactosylceramide level, suggesting a crosstalk between glucosylceramide synthase-and NCDase-mediated ceramide utiliz...

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Section: Knocking Down Ncdase Exacerbates Mitochondrial Dysfunction Imentioning

confidence: 90%

“…Mitochondrial dysfunction in type 1 diabetic heart tissue is the result of inhibition of the respiratory chain (33)(34)(35), oxidative stress ( 35,36 ), and decreased resistance to Ca 2+ - ( 37,38 ) and oxidative stressinduced mPTP opening ( 39,40 ).…”

Section: Antibodiesmentioning

confidence: 99%

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Novgorodov

Riley

et al. 2016

Journal of Lipid Research

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“…4), which correlated with enhanced ROS abundance (unpublished data). In the follow-up study by Williamson et al, the same IFM were more susceptible to apoptotic cell death, with increased caspase activation, decreased mitochondrial membrane potential, and increased susceptibility to mPTP opening with enhanced proapoptotic protein expression (141). The smaller or fragmented characteristic of the IFM purports mitochondrial morphology as a pathological marker of DCM, as these mitochondria are more susceptible to mitochondrial apoptosis and subsequent tissue damage.…”

mentioning

confidence: 94%

“…Aside from genetic models, chemical manipulation to ablate pancreatic b-cells has been used to induce a type 1 diabetic phenotype through STZ (34,73,96,141). The Hollander lab examined DCM in this model 5 weeks after the development of elevated blood glucose levels (34).…”

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confidence: 99%

Mitochondrial Morphology in Metabolic Diseases

Galloway

Yoon

2013

Antioxidants & Redox Signaling

111

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Significance: Mitochondria are the cellular energy-producing organelles and are at the crossroad of determining cell life and death. As such, the function of mitochondria has been intensely studied in metabolic disorders, including diabetes and associated maladies commonly grouped under all-inclusive pathological condition of metabolic syndrome. More recently, the altered metabolic profiles and function of mitochondria in these ailments have been correlated with their aberrant morphologies. This review describes an overview of mitochondrial fission and fusion machineries, and discusses implications of mitochondrial morphology and function in these metabolic maladies. Recent Advances: Mitochondria undergo frequent morphological changes, altering the mitochondrial network organization in response to environmental cues, termed mitochondrial dynamics. Mitochondrial fission and fusion mediate morphological plasticity of mitochondria and are controlled by membrane-remodeling mechanochemical enzymes and accessory proteins. Growing evidence suggests that mitochondrial dynamics play an important role in diabetes establishment and progression as well as associated ailments, including, but not limited to, metabolism-secretion coupling in the pancreas, nonalcoholic fatty liver disease progression, and diabetic cardiomyopathy. Critical Issues: While mitochondrial dynamics are intimately associated with mitochondrial bioenergetics, their cause-and-effect correlation remains undefined in metabolic diseases. Future Directions: The involvement of mitochondrial dynamics in metabolic diseases is in its relatively early stages. Elucidating the role of mitochondrial dynamics in pathological metabolic conditions will aid in defining the intricate form-function correlation of mitochondria in metabolic pathologies and should provide not only important clues to metabolic disease progression, but also new therapeutic targets. Antioxid. Redox Signal. 19,[415][416][417][418][419][420][421][422][423][424][425][426][427][428][429][430]

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“…Dutta et al (2006) discovered COX7B to be a mitochondrial electron transport chain gene whose expression was down-regulated in multiple sclerosis patients, leading to reduced ATP production and mitochondrial dysfunction. Mitochondrial dysfunction contributes to the development of cardiovascular diseases (including atherosclerosis) by inducing changes in the mitochondrial morphology and apoptosis (Williamson et al, 2010). Therefore, we speculated that cytochrome-c oxidases play a key role in the development of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Prediction of genetic risk factors of atherosclerosis using various bioinformatic tools

Wang

Zhao

2016

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to identify potential markers of atherosclerosis development in familial hypercholesterolemia (FH) patients. GSE13985 microarray data, generated using blood samples from 5 FH patients and 5 matched controls, was downloaded from the Gene Expression Omnibus. Differentially expressed genes (DEGs) between FH and controls were identified and a protein-protein interaction (PPI) network was constructed. Module and hub proteins were screened in this network. The module genes were subjected to a gene ontology (GO) analysis, and a Kyoto Encyclopedia of Genes and Genomes enrichment analysis was also performed. A total of 394 genes, including 125 up-and 269 down-regulated genes, were differentially expressed. Ribosomal proteins L9 (RPL9), L35 (RPL35), and S7 (RPS7) were designated as hub nodes in the PPI network. The DEGs were found to be significantly enriched in ribosomal and oxidative phosphorylation pathways. Ribosomal protein genes were found to be involved in the ribosomal pathway. The cytochrome-c oxidase (COX)

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Enhanced apoptotic propensity in diabetic cardiac mitochondria: influence of subcellular spatial location

Cited by 85 publications

References 49 publications

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Mitochondrial Morphology in Metabolic Diseases

Prediction of genetic risk factors of atherosclerosis using various bioinformatic tools

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