BACKGROUND: Recent evidence indicates that insulin resistance in skeletal muscle may be related to reduce mitochondrial number and oxidation capacity. However, it is not known whether increasing mitochondrial number and function improves insulin resistance. In the present study, we investigated the effects of a combination of nutrients on insulin resistance and mitochondrial biogenesis/function in skeletal muscle of type 2 diabetic Goto-Kakizaki rats. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrated that defect of glucose and lipid metabolism is associated with low mitochondrial content and reduced mitochondrial enzyme activity in skeletal muscle of the diabetic Goto-Kakizaki rats. The treatment of combination of R-alpha-lipoic acid, acetyl-L-carnitine, nicotinamide, and biotin effectively improved glucose tolerance, decreased the basal insulin secretion and the level of circulating free fatty acid (FFA), and prevented the reduction of mitochondrial biogenesis in skeletal muscle. The nutrients treatment also significantly increased mRNA levels of genes involved in lipid metabolism, including peroxisome proliferator-activated receptor-alpha (Ppar alpha), peroxisome proliferator-activated receptor-delta (Ppar delta), and carnitine palmitoyl transferase-1 (Mcpt-1) and activity of mitochondrial complex I and II in skeletal muscle. All of these effects of mitochondrial nutrients are comparable to that of the antidiabetic drug, pioglitazone. In addition, the treatment with nutrients, unlike pioglitazone, did not cause body weight gain. CONCLUSIONS/SIGNIFICANCE: These data suggest that a combination of mitochondrial targeting nutrients may improve skeletal mitochondrial dysfunction and exert hypoglycemic effects, without causing weight gain.

An increasing number of data demonstrate the utility of ketogenic diets in a variety of metabolic diseases as obesity, metabolic syndrome, and diabetes. In regard to neurological disorders, ketogenic diet is recognized as an effective treatment for pharmacoresistant epilepsy but emerging data suggests that ketogenic diet could be also useful in amyotrophic lateral sclerosis, Alzheimer, Parkinson's disease, and some mitochondriopathies. Although these diseases have different pathogenesis and features, there are some common mechanisms that could explain the effects of ketogenic diets. These mechanisms are to provide an efficient source of energy for the treatment of certain types of neurodegenerative diseases characterized by focal brain hypometabolism; to decrease the oxidative damage associated with various kinds of metabolic stress; to increase the mitochondrial biogenesis pathways; and to take advantage of the capacity of ketones to bypass the defect in complex I activity implicated in some neurological diseases. These mechanisms will be discussed in this review.

Abstract The present study addresses whether exercise during pregnancy in mouse alters mitochondrial function in the brains of the resultant offspring. We divided pregnant mice into 4 groups: a control group (CON), and groups of mice that exercised for 20 (E20m), 30 (E30m), and 40 min per day (E40m). The pregnant mice ran on a treadmill at 12 m/min, 5 days/week for a duration of 3 weeks. The protein expression of cytochrome c oxidase subunit Va (CVa) was downregulated in the offspring of the E20m group, unlike that in the control animals, while CVa expression was reservedin the E40m neonates. The F1-ATPase catalytic core (Core) protein expression levels were the highest in the E40m group neonates. Complex I, IV, and ATPase activities were significantly lower in the E20m group than that in the control group neonates and were reserved in the E30m and E40m group neonates. The activities of citrate synthase (CS) and pyruvate dehydrogenase (PDH) were consistent with those of complex I, IV, and ATPase. Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), mitochondrial transcription factor A (Tfam), nuclear respiratory factor-1 (NRF-1), and mitochondrial DNA (mtDNA) showed high levels of expression in the E40m neonates compared to the other groups. MDA levels in E40m neonates were higher than that in the controls, but were lower than that in the E20m neonates. Finally, 40min/day of maternal exercise improved mitochondrial function inthe resultant pups and was concomitant with brain-derived trophic factor induction in the hippocampus, thereby functionally improving short-term memory.

Quercetin is one of a broad group of natural polyphenolic flavonoid substances that are being investigated for their widespread health benefits. These benefits have generally been ascribed to its combination of antioxidant and anti-inflammatory activity, but recent in vitro evidence suggests that improved mitochondrial biogenesis could play an important role. In addition, the in vivo effects of quercetin on mitochondrial biogenesis exercise tolerance are unknown. We examined the effects of 7 days of quercetin feedings in mice on markers of mitochondrial biogenesis in skeletal muscle and brain, and on endurance exercise tolerance. Mice were randomly assigned to one of the following three treatment groups: placebo, 12.5 mg/kg quercetin, or 25 mg/kg quercetin. Following 7 days of treatment, mice were killed, and soleus muscle and brain were analyzed for mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC-1alpha) and sirtuin 1 (SIRT1), and mitochondrial DNA (mtDNA) and cytochrome c. Additional mice underwent a treadmill performance run to fatigue or were placed in voluntary activity wheel cages, and their voluntary activity (distance, time, and peak speed) was recorded. Quercetin increased mRNA expression of PGC-1alpha and SIRT1 (P<0.05), mtDNA (P<0.05) and cytochrome c concentration (P<0.05). These changes in markers of mitochondrial biogenesis were associated with an increase in both maximal endurance capacity (P<0.05) and voluntary wheel-running activity (P<0.05). These benefits of querectin on fitness without exercise training may have important implications for enhancement of athletic and military performance and may also extend to prevention and/or treatment of chronic diseases.

Mitochondrial diseases are rare metabolic disorders which can cause hypertrophic cardiomyopathy. We describe a 3-year-old girl who was diagnosed for mitochondrial disease (mutation m.5559A>G in the mitochondrial-tRNAgene (MT-TW)). Echocardiography showed left ventricular hypertrophy with an enlarged septum (9 mm, Z-score 3.26). Antioxidant supplementation associated with a high-fat ketogenic diet were introduced and improved, as expected, neurological status. In addition, heart parameters improved with a normalization of interventricular septum thickness at the age of six (6 mm, Z-score 1.05). This case report suggests that a ketogenic diet may improve hypertrophic cardiomyopathy in the context of mitochondrial disease.

Modulating mitochondrial antioxidant status is a nutritional issue of great interest in the treatment or prevention of several oxidative stress related diseases such as obesity. Thus, the aim of the present study was to analyze the effects of three antioxidants on hepatic mitochondrial function and antioxidant status. Isolated rat liver mitochondria were incubated with vitamin C, resveratrol and lipoic acid. The activity of antioxidant enzymes (manganese superoxide dismutase and glutathione peroxidase), ROS generation and respiratory parameters (RCR, P/O ratio and respiratory states) were measured. Vitamin C influenced mitochondrial function by decreasing of ROS generation (P<0.0001), by stimulating the activity of manganese superoxide dismutase (197.60± 35.99%; P<0.001) as well as glutathione peroxidase (15.70± 5.76%; P<0.05) and by altering the activity of the electron transport chain, mainly by decreasing the P/O ratio (P<0.05). Resveratrol induced a significant increase in manganese superoxide dismutase activity (160± 11.78%; P<0.0001) and a decrease in ROS generation (P<0.05 to P<0.0001). By contrast, lipoic acid inhibited glutathione peroxidase activity (16.48± 3.27%; P<0.05) and induced the uncoupling of the electron transport chain (P<0.01). Moreover, this antioxidant induced a strong decrease in the P/O ratio (P<0.05 to P<0.0001). In conclusion, our results suggest that the three tested antioxidants produced direct effects on mitochondrial function, although the magnitude and intensity of these actions were significantly different, which may have implications when administrated as antioxidants.