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Activation of ceramide‐metabolizing pathway in mitochondria from diabetic heart (758.3)
Author(s) -
Novgorodov Sergei,
Riley Christopher,
Gudz Tatyana
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.758.3
Subject(s) - ceramide , sphingolipid , mitochondrion , ceramide synthase , biology , endocrinology , microbiology and biotechnology , medicine , diabetic cardiomyopathy , atp synthase , biochemistry , enzyme , cardiomyopathy , heart failure , apoptosis
Mitochondrial dysfunction is an important contributor to the development of cardiac dysfunction in diabetic cardiomyopathy. Sphingolipids are key mediators of cell‐stress responses and effectors of mitochondrial function. The objective of the study was to investigate mechanisms underlying sphingolipid‐mediated mitochondrial dysfunction. The alterations of mitochondrial sphingolipid metabolism in cardiac mitochondria from mice with streptozotocin‐ induced type‐1 diabetes were examined. Sphingolipid analysis revealed profound increases in dihydroceramides in both subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria. However, ceramide levels have not changed. Analysis of sphingolipid‐metabolizing enzyme gene expression indicated that, of the 42 genes investigated, only four genes exhibited an up‐regulation of > 2 fold: acid ceramidase, dihydroceramide synthase 2, desaturase 1 and galactosidase. Increased dihydroceramide levels along with activation of desaturase1 and dihydroceramide synthase 2 are indicative of an activation of de novo ceramide biosynthesis in diabetic heart. However, the lack of an increase in ceramide suggests concomitant up‐regulation of ceramide‐metabolizing pathways. Indeed, knocking down mitochondria‐resident neutral ceramidase (NCDase) drastically increased ceramide level in both SSM and IFM mitochondria from diabetic hearts. Ceramide increase in mitochondria from diabetic NCDase KO mouse hearts correlated with concomitant decrease in mitochondrial calcium retention capacity and suppression of mitochondrial respiration. These data attest that diabetes increases ceramide flux in cardiac mitochondria, which is controlled at least in part by mitochondrial NCDase. Grant Funding Source : These studies were supported by grant from The American Diabetes Association (#7‐12‐IN‐28) to SN.