High fat, high sucrose diet causes cardiac mitochondrial dysfunction due in part to oxidative post-translational modification of mitochondrial complex II

Abstract

Background Diet-induced obesity leads to metabolic heart disease (MHD) characterized by increased oxidative stress that may cause oxidative post-translational modifications (OPTM) of cardiac mitochondrial proteins. The functional consequences of OPTM of cardiac mitochondrial proteins in MHD are unknown. Our objective was to determine whether cardiac mitochondrial dysfunction in MHD due to diet-induced obesity is associated with cysteine OPTM. Methods and results Male C57Bl/6J mice were fed either a high-fat, high-sucrose (HFHS) or control diet for 8 months. Cardiac mitochondria from HFHS-fed mice (vs. control diet) had an increased rate of H2O2 production, a decreased GSH/GSSG ratio, a decreased rate of complex II substrate-driven ATP synthesis and decreased complex II activity. Complex II substrate-driven ATP synthesis and complex II activity were partially restored ex-vivo by reducing conditions. A biotin switch assay showed that HFHS feeding increased cysteine OPTM in complex II subunits A (SDHA) and B (SDHB). Using iodo-TMT multiplex tags we found that HFHS feeding is associated with reversible oxidation of cysteines 89 and 231 in SDHA, and 100, 103 and 115 in SDHB. Conclusions MHD due to consumption of a HFHS “Western” diet causes increased H2O2 production and oxidative stress in cardiac mitochondria associated with decreased ATP synthesis and decreased complex II activity. Impaired complex II activity and ATP production are associated with reversible cysteine OPTM of complex II. Possible sites of reversible cysteine OPTM in SDHA and SDHB were identified by iodo-TMT tag labeling. Mitochondrial ROS may contribute to the pathophysiology of MHD by impairing the function of complex II.

Decaffeinated green tea extract rich in epigallocatechin-3-gallate prevents fatty liver disease by increased activities of mitochondrial respiratory chain complexes in diet-induced obesity mice

“…Complex III represents a confluence point for reducing equivalents from various dehydrogenases; it can catalyze the transfer of electrons from hydroxyquinones. This finding was in contrast to the striking observation of mitochondrial dysfunction in the liver from the high-fat induced mice without cathechins once there was a significant increase in activity of the II-III complexes in hyperlipidic group [13,61] (Figure 4). …”

“…Several studies in humans [36][37][38][39] and rodents [8,13,18,40,41] presented strong evidence that HFD, particularly rich in saturated fatty acids, promoted the development of three pathological features associated with the metabolic syndrome: dyslipidemia, insulin resistance/glucose intolerance, and increased visceral adiposity [42]. Our experimental model of diet to induce obesity proved to be effective in simulating obesity with treatment of 16 weeks.…”

“…A reduction in mitochondrial function may contribute to the increase in lipid accumulation leading to insulin resistance [10]. These modifications may be related to the reduction in maximal activities of enzyme systems, such as carnitine palmitoyl transferase and mitochondrial respiratory chain complexes, which are responsible for the transport of long chain fatty acids into the organelle and generation of ATP molecules, respectively [13,14]. All of these changes contribute to the exacerbation of fatty liver.…”

Hepatic proteome and its network response to supplementation of an anti-obesity herbal mixture in diet-induced obese mice

“…In addition, bioinformatics classification and network analysis were carried out to investigate functional connections between identified proteins and key fatty acid metabolic targets (AMPK, ACC, and FAS). It has been demonstrated that HFD intake leads to dietinduced obesity along with many disease risk factors in association with increased post-translational modification (PTM), production of advanced glycation end products, and apoptosis [46,47]. Our proteomic data confirmed five proteins having the same molecular weight but different pIs, indicating the proteins underwent PTM.…”

Solving mitochondrial mysteries

“…In addition to these state of the art review articles this special issue also contains several original research articles [27][28][29][30]. Taken together this special issue provides up to date reviews as well as original research articles on some of the hottest topics in mitochondrial biology.…”