Search

Obesity is associated with increased cardiovascular morbidity and mortality, but the effects of circulating factors on cardiac function is not fully elucidated. Present study aims to explore the pathophysiological role of microRNA (miR)-194, one of hepatic enriched miRs, in the process of obesity-related cardiomyopathy in human subjects and mice. The expression level of circulating exosomal miR-194 was measured in 39 lean and 35 obese human subjects, and correlated with cardiac parameters. The effects of miR-194 on mitochondrial activity and cardiac function were investigated by administration of miR-194 sponge in mouse cardiomyocytes and obesity-related cardiomyopathy. The upregulation of circulating miR-194 level was closely correlated with impaired human cardiac function, including ejection fraction (r = -0.5002, p < 0.01) and NT-proBNP levels (r = 0.3670, p < 0.01). Exosomes from obese mice impaired myocyte mitochondrial activity, but blocking with miR-194 sponge attenuated the exosomal miR-194-induced reduction of ATP production (p < 0.05), basal oxygen consumption (p < 0.01) and mitochondrial complex I activity (p < 0.001). In vivo mouse study, high fat diet damaged cardiac function, normal structure and mitochondrial activity, whereas miR-194 sponge improved the cardiac status. Present study uncovered the correlation between circulating miR-194 and cardiac parameters in human subjects, and provided solid evidence of the therapeutic application of miR-194 sponge in combating obesity-mediated cardiac dysfunction., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Haplogroup G predisposes one to an increased risk of osteoarthritis (OA) occurrence, while haplogroup B4 is a protective factor against OA onset. However, the underlying mechanism is not known. Here, by using trans-mitochondrial technology, we demonstrate that the activity levels of mitochondrial respiratory chain complex I and III are higher in G cybrids than in haplogroup B4. Increased mitochondrial oxidative phosphorylation (OXPHOS) promotes mitochondrial-related ATP generation in G cybrids, thereby shifting the ATP generation from glycolysis to OXPHOS. Furthermore, we found that lower glycolysis in G cybrids decreased cell viability under hypoxia (1% O2) compared with B4 cybrids. In contrast, G cybrids have a lower NAD(+)/NADH ratio and less generation of reactive oxygen species (ROS) under both hypoxic (1% O2) and normoxic (20% O2) conditions than B4 cybrids, indicating that mitochondrial-mediated signaling pathways (retrograde signaling) differ between these cybrids. Gene expression profiling of G and B4 cybrids using next-generation sequencing technology showed that 404 of 575 differentially expressed genes (DEGs) between G and B4 cybrids are enriched in 17 pathways, of which 11 pathways participate in OA. Quantitative reverse transcription PCR (qRT-PCR) analyses confirmed that G cybrids had lower glycolysis activity than B4 cybrids. In addition, we confirmed that the rheumatoid arthritis pathway was over-activated in G cybrids, although the remaining 9 pathways were not further tested by qRT-PCR. In conclusion, our findings indicate that mtDNA haplogroup G may increase the risk of OA by shifting the metabolic profile from glycolysis to OXPHOS and by over-activating OA-related signaling pathways., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The 4977 bp common deletion is one of the most frequently observed mitochondrial DNA (mtDNA) mutations in human tissues and has been implicated in various human cancer types. It is generally believed that continuous generation of intracellular reactive oxygen species (ROS) during oxidative phosphorylation (OXPHOS) is a major underlying mechanism for generation of such mtDNA deletions while antioxidant systems, including Manganese superoxide dismutase (MnSOD), mitigating the deleterious effects of ROS. However, the clinical significance of this common deletion remains to be explored. A comprehensive investigation on occurrence and accumulation of the common deletion and mtDNA copy number was carried out in breast carcinoma (BC) patients, benign breast disease (BBD) patients and age-matched healthy donors in our study. Meanwhile, the representative oxidative (ROS production, mtDNA and lipid oxidative damage) and anti-oxidative features (MnSOD expression level and variation) in blood samples from these groups were also analyzed. We found that the mtDNA common deletion is much more likely to be detected in BC patients at relatively high levels while the mtDNA content is lower. This alteration has been associated with a higher MnSOD level and higher oxidative damages in both BC and BBD patients. Our results indicate that the mtDNA common deletion in blood may serve a biomarker for the breast cancer., (Copyright © 2015 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Mitochondrial dysfunction has been long proposed to play a major role in tumorigenesis. Mitochondrial DNA (mtDNA) mutations, especially the mtDNA 4,977 bp deletion has been found in patients of various types of cancer. In order to comprehend the mtDNA 4,977 bp deletion status in various cancer types, we performed a meta-analysis composed of 33 publications, in which a total of 1613 cancer cases, 1516 adjacent normals and 638 healthy controls were included. When all studies were pooled, we found that cancerous tissue carried a lower mtDNA 4,977 bp deletion frequency than adjacent non-cancerous tissue (OR = 0.43, 95% CI = 0.20-0.92, P = 0.03 for heterogeneity test, I(2) = 91.5%) among various types of cancer. In the stratified analysis by cancer type the deletion frequency was even lower in tumor tissue than in adjacent normal tissue of breast cancer (OR = 0.19, 95% CI = 0.06-0.61, P = 0.005 for heterogeneity test, I(2)= 82.7%). Interestingly, this observation became more significant in the stratified studies with larger sample sizes (OR = 0.70, 95% CI = 0.58-0.86, P = 0.0005 for heterogeneity test, I(2) = 95.1%). Furthermore, when compared with the normal tissue from the matched healthy controls, increased deletion frequencies were observed in both adjacent non-cancerous tissue (OR = 3.02, 95% CI = 2.13-4.28, P<0.00001 for heterogeneity test, I(2)= 53.7%), and cancerous tissue (OR = 1.36, 95% CI = 1.04-1.77, P = 0.02 for heterogeneity test, I(2)= 83.5%). This meta-analysis suggests that the mtDNA 4,977 bp deletion is often found in cancerous tissue and thus has the potential to be a biomarker for cancer occurrence in the tissue, but at the same time being selected against in various types of carcinoma tissues. Larger and better-designed studies are still warranted to confirm these findings.

Emerging evidence suggests that microRNAs (miRNAs) are essential for metabolic haemostasis of liver tissues. Among them, miR‐33a is supposed to modulate the cholesterol export and fatty acid oxidation, but whether miR‐33a involves in the process of fatty liver disease is unclear. To disclose the hypothesis, we utilized miR‐33a mimic and antisense to explore their effects in primary hepatocytes or high‐fat diet (HFD)‐fed mice. Treatment with palmitic acid (PA) or HFD significantly increased the expression of miR‐33a in hepatocytes or liver tissues. In primary hepatocytes, miR‐33a mimic decreased mitochondrial function, including reduction of ATP production and oxygen consumption, whereas miR‐33a inhibition protected PA‐induced mitochondrial dysfunction. Interestingly, miR‐33a selectively suppressed mitochondrial complex I activity and protein expression, but not other complexes. Through bioinformatics prediction, we found miR‐33a directly targeted on the 3′‐UTR of NDUFA5. Dual‐luciferase reporter analysis further confirmed the direct suppression of miR‐33a on NDUFA5 expression. More importantly, administration of miR‐33a antisense could effectively restore HFD‐induced mitochondrial dysfunction through up‐regulation of NDUFA5 levels. Mice treated with miR‐33a antisense also exhibited improved liver function and structural disorders under obese status. Taken together, miR‐33a was an important mediator of hepatocyte mitochondrial function, and the therapeutic benefits implied miR‐33a antisense had the potential clinical application in combating the fatty liver disease. [ABSTRACT FROM AUTHOR]