Mitochondrial DNA Damage and Dysfunction, and Oxidative Stress Are Associated with Endoplasmic Reticulum Stress, Protein Degradation and Apoptosis in High Fat Diet-Induced Insulin Resistance Mice

Abstract

BackgroundRecent studies showed a link between a high fat diet (HFD)-induced obesity and lipid accumulation in non-adipose tissues, such as skeletal muscle and liver, and insulin resistance (IR). Although the mechanisms responsible for IR in those tissues are different, oxidative stress and mitochondrial dysfunction have been implicated in the disease process. We tested the hypothesis that HFD induced mitochondrial DNA (mtDNA) damage and that this damage is associated with mitochondrial dysfunction, oxidative stress, and induction of markers of endoplasmic reticulum (ER) stress, protein degradation and apoptosis in skeletal muscle and liver in a mouse model of obesity-induced IR.Methodology/Principal FindingsC57BL/6J male mice were fed either a HFD (60% fat) or normal chow (NC) (10% fat) for 16 weeks. We found that HFD-induced IR correlated with increased mtDNA damage, mitochondrial dysfunction and markers of oxidative stress in skeletal muscle and liver. Also, a HFD causes a change in the expression level of DNA repair enzymes in both nuclei and mitochondria in skeletal muscle and liver. Furthermore, a HFD leads to activation of ER stress, protein degradation and apoptosis in skeletal muscle and liver, and significantly reduced the content of two major proteins involved in insulin signaling, Akt and IRS-1 in skeletal muscle, and Akt in liver. Basal p-Akt level was not significantly influenced by HFD feeding in skeletal muscle and liver.Conclusions/SignificanceThis study provides new evidence that HFD-induced mtDNA damage correlates with mitochondrial dysfunction and increased oxidative stress in skeletal muscle and liver, which is associated with the induction of markers of ER stress, protein degradation and apoptosis.

Pomegranate and green tea extracts protect against ER stress induced by a high-fat diet in skeletal muscle of mice

“…Consistent with a recent report [53], protein carbonyls were increased in muscle after a HFD. This increase was associated with an elevation of NOX2 and NOX4 (NADPH oxidase isoforms) mRNA levels, confirming the presence of an oxidative stress in skeletal muscle after HFD.…”

“…Accordingly, we found that HFD increased MURF1 and MAFbx mRNA. This observation supports an up-regulation of the ubiquitin-proteasome system and is consistent with a recent study reporting a higher level of ubiquitinated proteins in muscle after HFD [53]. Moreover, the increase of MURF1 and MAFbx was largely repressed by pomegranate or green tea extracts.…”

Oxidative Damage Modeling by Biomonitoring of Exposure to Metals for Manual Metal Arc Welders

“…Exposure to metals in welders has been reported frequently (5,31). The base of this study was oxidative damage and MDA production in metals-exposed population (15,16). Since lipid peroxidation produces MDA (32), we measured the excretion of MDA in urine of MMAW worker from a PTM factory for oxidative damage estimation.…”

“…ROS) and antioxidant defense in cells. Oxidative stress target wide range of macromolecules including nucleic acids (15) and proteins (16), which mediates the induction of several pathogeneses. It has been documented that metals-induced damage can be related to oxidative stress generation (17)(18)(19).…”

Reactive Oxygen Species and Oxidative Stress in Obesity

“…Mitokondriyal ADP'nin azalması oksidatif fosforilasyon hızını düşürür ve mitokondriyal uncoupling elektron akışını ve serbest radikal oluşumu-nu artırır. Obeziteye bağlı DNA zedelenmesi, protein katlanması, lipit damlası oluşumu ve hepatik kolesterol birikmesi ile eşleştirilen mitokondriyal disfonksiyon, oksidatif stres, ve endoplazmik retikulum (ER) stresine neden olur (30,40). Fizyolojik koşullarda ER'nin oksidasyonu ile proteinlerin yanlış katlanması, "yanlış katlanmış protein yanıtı'nı aktive eder.…”