Alterations in mitochondrial aconitase activity and respiration, and in concentration of citrate in some organs of mice with experimental or genetic diabetes

Boquist, Lennart; Ericsson, I.; Lorentzon, Ronny; Nelson, Lennart

doi:10.1016/0014-5793(85)80979-0

Cited by 25 publications

(9 citation statements)

References 17 publications

(13 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…*Significance of P Ͻ 0.05; **significance of P Ͻ 0.01; ***significance of P Ͻ 0.001. (7). Production of reactive oxygen species is particularly detrimental in the absence of sufficient antioxidant enzyme capacity in the EDL, as reported previously in the literature (43) and confirmed in our experiments.…”

Section: E662 Early Diabetes and Mitochondrial Dysfunction In Musclesupporting

confidence: 90%

Early mitochondrial dysfunction in glycolytic muscle, but not oxidative muscle, of the fructose-fed insulin-resistant rat

Warren

Lou

Lucchinetti

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Although evidence that type 2 diabetes mellitus (T2DM) is accompanied by mitochondrial dysfunction in skeletal muscle has been accumulating, a causal link between mitochondrial dysfunction and the pathogenesis of the disease remains unclear. Our study focuses on an early stage of the disease to determine whether mitochondrial dysfunction contributes to the development of T2DM. The fructose-fed (FF) rat was used as an animal model of early T2DM. Mitochondrial respiration and acylcarnitine species were measured in oxidative (soleus) and glycolytic [extensor digitorum longus (EDL)] muscle. Although FF rats displayed characteristic signs of T2DM, including hyperglycemia, hyperinsulinemia, and hypertriglyceridemia, mitochondrial content was preserved in both muscles from FF rats. The EDL muscle had reduced complex I and complex I and II respiration in the presence of pyruvate but not glutamate. The decrease in pyruvate-supported respiration was due to a decrease in pyruvate dehydrogenase activity. Accumulation of C14:1 and C14:2 acylcarnitine species and a decrease in respiration supported by long-chain acylcarnitines but not acetylcarnitine indicated dysfunctional ␤-oxidation in the EDL muscle. In contrast, the soleus muscle showed preserved mitochondrial respiration, pyruvate dehydrogenase activity, and increased fatty acid oxidation, as evidenced by overall reduced acylcarnitine levels. Aconitase activity, a sensitive index of reactive oxygen species production in mitochondria, was reduced exclusively in EDL muscle, which showed lower levels of the antioxidant enzymes thioredoxin reductase and glutathione peroxidase. Here, we show that the glycolytic EDL muscle is more prone to an imbalance between energy supply and oxidation caused by insulin resistance than the oxidative soleus muscle. insulin resistance; type 2 diabetes; mitochondrial dysfunction; skeletal muscle; fatty acid oxidation; aconitase; sirtuin-3 WORLDWIDE, THE PREVALENCE OF TYPE 2 DIABETES MELLITUS (T2DM) has reached epidemic proportions, which is due largely to increasing age and increasing incidence of obesity (21). Insulin resistance is a major characteristic of T2DM and refers to the inability of cells to respond adequately to insulin, which consequently leads to impaired glucose uptake, reduced glucose clearance, and hyperinsulinemia (15, 51). Because about 80% of glucose uptake in the postprandial state occurs in skeletal muscle, skeletal muscle is the largest "glucose sink" in the body, and therefore, it is considered a key player in the pathogenesis of insulin resistance. Although many studies demonstrate that mitochondrial dysfunction may accompany insulin resistance in skeletal muscle, the role of mitochondrial dysfunction in the pathogenesis of T2DM remains unclear. The difficulty lies in determining exactly which aspects of mitochondrial dysfunction are involved as well as the chronology of mitochondrial/cellular events that lead to T2DM (39, 44).The primary function of mitochondria is ATP production via oxidative phosphorylation (OXPHOS)...

show abstract

Section: E662 Early Diabetes and Mitochondrial Dysfunction In Musclesupporting

confidence: 90%

Early mitochondrial dysfunction in glycolytic muscle, but not oxidative muscle, of the fructose-fed insulin-resistant rat

Warren

Lou

Lucchinetti

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

show abstract

“…Carnitine palmitoyltransferases 1 and 2 (CPTs; EC: 2.3.1.21) were found to be the key enzymes in the import of long-chain fatty acids into mitochondria and recently have received considerable attention due to their catalytic activity and for the development of novel drugs against diabetes (Rufer et al, 2006). Aconitase is an alternative name for Aconitate hydratase, and both indicate the same enzyme that is associated with diabetes (Boquist et al, 1985). Though the exact connection is still not fully known, studies have shown that lower aconitase activity is responsible for influencing the rates of the activity of the tricarboxylic acid cycle, thereby impairing mitochondrial function and energy metabolism in diabetic hearts (Lin et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Rediscovering Medicinal Plants' Potential with OMICS: Microsatellite Survey in Expressed Sequence Tags of Eleven Traditional Plants with Potent Antidiabetic Properties

Sahu

Sen

Choudhury

et al. 2014

OMICS: A Journal of Integrative Biology

View full text Add to dashboard Cite

Herbal medicines and traditionally used medicinal plants present an untapped potential for novel molecular target discovery using systems science and OMICS biotechnology driven strategies. Since up to 40% of the world's poor people have no access to government health services, traditional and folk medicines are often the only therapeutics available to them. In this vein, North East (NE) India is recognized for its rich bioresources. As part of the Indo-Burma hotspot, it is regarded as an epicenter of biodiversity for several plants having myriad traditional uses, including medicinal use. However, the improvement of these valuable bioresources through molecular breeding strategies, for example, using genic microsatellites or Simple Sequence Repeats (SSRs) or Expressed Sequence Tags (ESTs)-derived SSRs has not been fully utilized in large scale to date. In this study, we identified a total of 47,700 microsatellites from 109,609 ESTs of 11 medicinal plants (pineapple, papaya, noyontara, bitter orange, bermuda brass, ratalu, barbados nut, mango, mulberry, lotus, and guduchi) having proven antidiabetic properties. A total of 58,159 primer pairs were designed for the non-redundant 8060 SSRpositive ESTs and putative functions were assigned to 4483 unique contigs. Among the identified microsatellites, excluding mononucleotide repeats, di-/trinucleotides are predominant, among which repeat motifs of AG/CT and AAG/CTT were most abundant. Similarity search of SSR containing ESTs and antidiabetic gene sequences revealed 11 microsatellites linked to antidiabetic genes in five plants. GO term enrichment analysis revealed a total of 80 enriched GO terms widely distributed in 53 biological processes, 17 molecular functions, and 10 cellular components associated with the 11 markers. The present study therefore provides concrete insights into the frequency and distribution of SSRs in important medicinal resources. The microsatellite markers reported here markedly add to the genetic stock for cross transferability in these plants and the literature on biomarkers and novel drug discovery for common chronic diseases such as diabetes.

show abstract

“…This suggests that hyperglycemia-induced superoxide generation rapidly inhibits the TCA cycle and that this is a metabolic effect unrelated to osmotic stress. There is some evidence that aconitase is decreased in animal models of diabetes (34), but this enzyme is not widely studied in vivo, probably because it is difficult to extract intact.…”

Section: Discussionmentioning

confidence: 99%

Short‐term hyperglycemia produces oxidative damage and apoptosis in neurons

et al. 2005

View full text Add to dashboard Cite

Dorsal root ganglia neurons in culture die through programmed cell death when exposed to elevated glucose, providing an in vitro model system for the investigation of the mechanisms leading to diabetic neuropathy. This study examines the time course of programmed cell death induction, regulation of cellular antioxidant capacity, and the protective effects of antioxidants in neurons exposed to hyperglycemia. We demonstrate that the first 2 h of hyperglycemia are sufficient to induce oxidative stress and programmed cell death. Using fluorimetric analysis of reactive oxygen species (ROS) production, in vitro assays of antioxidant enzymes, and immunocytochemical assays of cell death, we demonstrate superoxide formation, inhibition of aconitase, and lipid peroxidation within 1 h of hyperglycemia. These are followed by caspase-3 activation and DNA fragmentation. Antioxidant potential increases by 3-6 h but is insufficient to protect these neurons. Application of the antioxidant alpha-lipoic acid potently prevents glucose-induced oxidative stress and cell death. This study identifies cellular therapeutic targets to prevent diabetic neuropathy. Since oxidative stress is a common feature of the micro- and macrovascular complications of diabetes, the present findings have broad application to the treatment of diabetic patients.

show abstract

Alterations in mitochondrial aconitase activity and respiration, and in concentration of citrate in some organs of mice with experimental or genetic diabetes

Cited by 25 publications

References 17 publications

Early mitochondrial dysfunction in glycolytic muscle, but not oxidative muscle, of the fructose-fed insulin-resistant rat

Early mitochondrial dysfunction in glycolytic muscle, but not oxidative muscle, of the fructose-fed insulin-resistant rat

Rediscovering Medicinal Plants' Potential with OMICS: Microsatellite Survey in Expressed Sequence Tags of Eleven Traditional Plants with Potent Antidiabetic Properties

Short‐term hyperglycemia produces oxidative damage and apoptosis in neurons

Contact Info

Product

Resources

About