Category: mitochondria


Abstract

Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α has been shown to play critical roles in regulating mitochondria biogenesis, respiration, and muscle oxidative phenotype. Furthermore, reductions in the expression of PGC-1α in muscle have been implicated in the pathogenesis of type 2 diabetes. To determine the effect of increased muscle-specific PGC-1α expression on muscle mitochondrial function and glucose and lipid metabolism in vivo, we examined body composition, energy balance, and liver and muscle insulin sensitivity by hyperinsulinemic-euglycemic clamp studies and muscle energetics by using 31P magnetic resonance spectroscopy in transgenic mice. Increased expression of PGC-1α in muscle resulted in a 2.4-fold increase in mitochondrial density, which was associated with an ≈60% increase in the unidirectional rate of ATP synthesis. Surprisingly, there was no effect of increased muscle PGC-1α expression on whole-body energy expenditure, and PGC-1α transgenic mice were more prone to fat-induced insulin resistance because of decreased insulin-stimulated muscle glucose uptake. The reduced insulin-stimulated muscle glucose uptake could most likely be attributed to a relative increase in fatty acid delivery/triglyceride reesterfication, as reflected by increased expression of CD36, acyl-CoA:diacylglycerol acyltransferase1, and mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase, that may have exceeded mitochondrial fatty acid oxidation, resulting in increased intracellular lipid accumulation and an increase in the membrane to cytosol diacylglycerol content. This, in turn, caused activation of PKCθ, decreased insulin signaling at the level of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and skeletal muscle insulin resistance.

FULL ARTICLE: http://www.pnas.org/content/105/50/19926.full.pdf+html

 

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Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) is the founding member of a family of transcriptional coactivators that also includes PGC-1β (also called PERC) and PGC-1-related coactivator (reviewed in Puigserver and Spiegelman, 2003). PGC-1α is expressed in heart, kidney, brown adipose tissue (BAT), and brain and was originally described as a cold-inducible coactivator controlling adaptive thermogenesis in BAT and skeletal muscle by stimulating mitochondrial biogenesis and oxidative metabolism. Fasting induces hepatic PGC-1α expression thereby increasing gluconeogenesis, whereas in skeletal and cardiac muscle exercise increases PGC-1α, mitochondrial biogenesis, and respiration. Thus, PGC-1α expression seems finely tuned to reflect the cellular energy needs, with conditions of increased energy demands, such as cold, physical activity, or fasting inducing its expression. PGC-1α accomplishes these diverse functions through activating nuclear receptors like the PPARs, thyroid hormone receptors (TR), estrogen-related receptors (ERR), glucocorticoid receptor (GR) and hepatocyte nuclear factor (HNF) 4α, and other transcription factors, including nuclear respiratory factors (NRF) and FOXO1 (Figure 1). PGC-1α is dependent on other coregulators like the steroid receptor coactivator-1 (SRC-1) for its activity [Puigserver et al. 1999] and [Picard et al. 2002] .


Figure 1.

Schematic Representation of the Different Functions of PGC-1α in Its Target Tissues

See text for explanation.

Lin and coworkers now report in Cell the phenotypic analysis of PGC-1α−/− mice, which illustrates the diversity of PGC-1α physiology (Lin et al., 2004). The high postnatal mortality in PGC-1α−/− mice already underscores its importance for survival. Future studies are required to determine the cause of excessive neonatal death. Interestingly, gluconeogenesis is constitutively activated and uncoupled of nutritional status in surviving PGC-1α−/− mice. This constitutive activation of gluconeogenesis was subsequent to the induction of gluconeogenic genes by the elevated levels of C/EBPβ. These in vivo data are in apparent conflict with the predictions made from their in vitro studies and the defective gluconeogenesis in isolated PGC-1α−/− hepatocytes (Lin et al., 2004). Furthermore, acute adenoviral-mediated downmodulation of hepatic PGC-1α with small interfering RNA (RNAi) was reported to decrease gluconeogenesis leading to fasting hypoglycemia (Koo et al., 2004). The studies in PGC-1α−/−hepatocytes and with adenovirus-mediated PGC-1α RNAi address, however, acute hepatic depletion of PGC-1α, which is in contrast to the studies in animals with a genetic PGC-1α deficiency in all tissues. In such animals, both chronic compensation, as well as signals of nonhepatic PGC-1α-deficient tissues, are confounders. Temporally and spatially controlled PGC-1α mutants will be useful to clarify this issue.

PGC-1α−/− mice also have reduced mitochondrial function and defects in oxidative phosphorylation (OXPHOS). This is not only reflected by abnormal gluconeogenesis, which is dependent on ATP generated by OXPHOS, but also by impaired cold resistance. Adaptive thermogenesis in rodents is mainly a function of BAT in which mitochondrial oxidation is partially uncoupled of energy production through the action of uncoupling protein 1 (UCP-1). UCP-1 expression is reduced in PGC-1α−/− BAT. Furthermore, PGC-1α−/− mice have severe defects in expression of genes involved in OXPHOS and mitochondrial function in muscle. This muscle energy (ATP) deficit is further underscored by the activation of AMP-activated protein kinase subsequent to the reduced cellular ATP/AMP ratio. Paradoxically, whereas in man a decrease in PGC-1α, OXPHOS genes, and impaired mitochondrial activity in muscle has been linked with obesity, insulin resistance and predisposition to diabetes (Petersen et al., 2004 and references therein), PGC-1α−/− mice are lean and resistant to diet-induced obesity reflective of a substantial increase in energy expenditure. How can we explain this?

Energy expenditure is accounted for by adaptive thermogenesis and physical activity. In the wake of the decreased mitochondrial function and adaptive thermogenesis in PGC-1α−/− mice, the most likely culprit to explain the increased energy expenditure is an increased physical activity. In addition to being hyperactive, PGC-1α−/− mice also have behavioral abnormalities, stimulus-induced myoclonus, exaggerated startle responses, dystonic posturing, frequent limb clasping, and showed spongiform lesions in striatum and brain stem. Both these clinical and pathological findings are reminiscent of neurodegenerative disorders of movement, most notably of Huntington’s disease (HD), an autosomal dominant degenerative brain disorder, characterized by choreiform movements and dementia, that begins in adulthood and neuropathologically strikes the striatum. HD is the consequence of an expansion of CAG trinucleotide repeats occurring in the open reading frame of huntingtin, now encoding a protein with an expanded polyglutamine (polyQ) tract. Interestingly, homozygous and heterozygous HD patients have similar phenotypes, suggesting that the gain of function of huntingtin is toxic to neurons. The leading hypothesis to explain the HD phenotype is that the expanded polyQ tract in huntingtin interferes with other cellular processes, such as mitochondrial function. Mitochondrial dysfunction has since a long-time been linked with neurodegenerative diseases, a finding again highlighted by the decreased expression of mitochondrial genes in PGC-1α−/− mice. Other coregulators such as the CREB binding protein (CBP), the mammalian Sir2 homolog SIRT1, and TAFII130 have been linked with neurobehavioral abnormalities and neurodegeneration (Araki et al., 2004). In view of this, the role of PGC-1α and other coregulators with impact on energy homeostasis should be carefully explored in neurodegenerative diseases.

From a therapeutic perspective, PGC-1α−/− mice further validate the notion that stimulation of mitochondrial activity could be useful in the context of diseases such as obesity and associated metabolic disorders. It is interesting to note that an increase in physical activity and dietary restriction, the cornerstone of the therapy of obesity and metabolic syndrome, are both inducing PGC-1α activity. The molecular mechanism through which exercise and dietary restriction induce PGC-1α activity are not known in detail, however, several signaling pathways are being proposed. These include protein kinase A subsequent to activation of G protein-coupled receptors such as the glucagon and β3-adrenergic receptor, calcium/calmodulin-dependent protein kinase IV and calcineurin A, p38 mitogen-activated protein kinase (reviewed in [Puigserver and Spiegelman 2003] and [Kelly and Scarpulla 2004] ), S6 kinase 1, an effector of mammalian target of rapamycin, acting in an ancient nutrient-sensing signaling pathway (Um et al., 2004), and cyclin T1/cyclin-dependent kinase 9 (Sano et al., 2004). Whereas the above pathways directly target PGC-1α, another potential avenue consist of developing so-called selective nuclear receptor modulators that favor the recruitment of particular cofactors (e.g., PGC-1α, SRC-1) to nuclear receptors, as to induce a distinct and favorable biological response such as mitochondrial activation (Picard et al., 2002). Examples of nuclear receptors involved in energy homeostasis for which such modulators may be useful include the PPARs and ERRα. Finally other signaling pathways, perhaps working in parallel with PGC-1α to enhance mitochondrial activity, such as stimulating local generation of the TR ligand 3,5,3′-triiodothyronine through the induction of type 2 iodothyronine deiodinase, must be explored. It is clear that research on PGC-1α has energized the entire mitochondria field and has increased the chances that strategies to turbocharge mitochondrial activity may one day translate into therapies not only for metabolic disease, but perhaps also for certain cardiac problems and neurodegenerative diseases.

Sibutramine boosts metabolism and therefore also calorie burning, and suppresses appetite. It used to go by the trade name Meridia. Sibutramine was fairly effective, but was banned after studies indicated that its use led to cardiovascular disease. When the Italians did their experiment, in which they gave 254 men and women with diabetes-2 a daily 10 mg sibutramine for a year, sibutramine was still a legal substance.

Because L-carnitine has theoretically purely beneficial effects for diabetes sufferers, the researchers wanted to learn about the effects of a combination of sibutramine and carnitine. So they gave half of their subjects sibutramine only, and the other half 2 g L-carnitine a day in addition.

In the course of the year the sibutramine group lost 9.1 kg; the carnitine-sibutramine group lost 10.9 kg. The combined group not only lost more weight, they also appeared to become more sensitive to insulin.

 HbA1c = glycated haemoglobin, a marker for diabetes; FPG = fasting plasma glucose; PPG = postprandial plasma glucose; HOMA-IR = homeostasis model assessment of insulin resistance index fasting plasma insulin.

 

 

L-carnitine supplementation resulted in an increased production of the ‘good’ fat cell hormone adiponectin, and reduced the production of the inflammatory factor TNF-alpha. This would suggest that L-carnitine reduced the inflammatory reactions that diabetes-2 causes.

 And there were no side effects among the group that were given L-carnitine. For the record: the research was not funded by an L-carnitine manufacturer, but by the university that employs the researchers.

Effects of combination of sibutramine and L-carnitine compared with sibutramine monotherapy on inflammatory parameters in diabetic patients

Abstract

The aim of the study was to evaluate the effects of 12-month treatment with sibutramine plus l-carnitine compared with sibutramine alone on body weight, glycemic control, insulin resistance, and inflammatory state in type 2 diabetes mellitus patients. Two hundred fifty-four patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA1c] >8.0%) in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomized to take sibutramine 10 mg plus l-carnitine 2 g or sibutramine 10 mg in monotherapy. We evaluated at baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index, HbA1c, fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance index, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, tumor necrosis factor–α, adiponectin, vaspin, and high-sensitivity C-reactive protein. Sibutramine plus l-carnitine gave a faster improvement of fasting plasma glucose, postprandial plasma glucose, lipid profile, leptin, tumor necrosis factor–α, and high-sensitivity C-reactive protein compared with sibutramine alone. Furthermore, there was a better improvement of body weight, HbA1c, fasting plasma insulin, homeostasis model assessment of insulin resistance index, vaspin, and adiponectin with sibutramine plus l-carnitine compared with sibutramine alone. Sibutramine plus l-carnitine gave a better and faster improvement of all the analyzed parameters compared with sibutramine alone without giving any severe adverse effect.

ABSTRACT

The mitochondrion is at the core of cellular energy metabolism, being the site of most ATP generation. Calcium is a key regulator of mitochondrial function and acts at several levels within the organelle to stimulate ATP synthesis. However, the dysregulation of mitochondrial Ca2+ homeostasis is now recognized to play a key role in several pathologies. For example, mitochondrial matrix Ca2+ overload can lead to enhanced generation of reactive oxygen species, triggering of the permeability transition pore, and cytochrome c release, leading to apoptosis. Despite progress regarding the independent roles of both Ca2+ and mitochondrial dysfunction in disease, the molecular mechanisms by which Ca2+ can elicit mitochondrial dysfunction remain elusive. This review highlights the delicate balance between the positive and negative effects of Ca2+ and the signaling events that perturb this balance. Overall, a “two-hit” hypothesis is developed, in which Ca2+ plus another pathological stimulus can bring about mitochondrial dysfunction.

mitochondria; reactive oxygen species; free radicals; apoptosis; neurodegeneration; ischemia; permeability transition

Abstract

Average human life expectancy has progressively increased over many decades largely due to improvements in nutrition, vaccination, antimicrobial agents, and effective treatment/prevention of cardiovascular disease, cancer, etc. Maximal life span, in contrast, has changed very little. Caloric restriction (CR) increases maximal life span in many species, in concert with improvements in mitochondrial function. These effects have yet to be demonstrated in humans, and the duration and level of CR required to extend life span in animals is not realistic in humans. Physical activity (voluntary exercise) continues to hold much promise for increasing healthy life expectancy in humans, but remains to show any impact to increase maximal life span. However, longevity in Caenorhabditis elegans is related to activity levels, possibly through maintenance of mitochondrial function throughout the life span. In humans, we reported a progressive decline in muscle mitochondrial DNA abundance and protein synthesis with age. Other investigators also noted age-related declines in muscle mitochondrial function, which are related to peak oxygen uptake. Long-term aerobic exercise largely prevented age-related declines in mitochondrial DNA abundance and function in humans and may increase spontaneous activity levels in mice. Notwithstanding, the impact of aerobic exercise and activity levels on maximal life span is uncertain. It is proposed that age-related declines in mitochondrial content and function not only affect physical function, but also play a major role in regulation of life span. Regular aerobic exercise and prevention of adiposity by healthy diet may increase healthy life expectancy and prolong life span through beneficial effects at the level of the mitochondrion.

FULL ARTICLE IN PDF: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801852/pdf/424_2009_Article_724.pdf