Mitochondrial Function In Patients Research Articles

Development Of t-MDS In Patients Undergoing Autologous Transplantation For Lymphoma Is Not Associated With Increased Frequency Of Mitochondrial DNA Mutations

Therapy-related myelodysplasia/acute myeloid leukemia (t-MDS) is a lethal complication of cytotoxic cancer treatment. The incidence of t-MDS is particularly high in patients undergoing autologous hematopoietic cell transplantation (aHCT) for Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL). To better understand pathogenetic mechanisms underlying development of t-MDS we are prospectively following a cohort of patients undergoing aHCT for lymphoma at our center. In previous studies using samples from this cohort we identified altered expression of genes related to mitochondrial function in pre-aHCT samples from lymphoma patients who later developed t-MDS (cases) compared to patients from the cohort who did not develop t-MDS (controls) (Cancer Cell 2011 20:591). Altered mitochondrial gene expression was associated with increased levels of mitochondrial reactive oxygen species (ROS) in samples from patients who subsequently developed t-MDS. These results suggest a possible role for mitochondrial dysfunction and increased ROS in pathogenesis of t-MDS. Somatic mutations of mitochondria DNA (mtDNA) are observed at increased frequency in many malignant conditions. Somatic mtDNA mutations may reflect increased susceptibility to mutagenesis, and could contribute to altered mitochondrial function in patients with t-MDS.Here we sought to investigate the role of mitochondrial genomic instability in t-MDS development by analyzing the mutation profile of mtDNA in hematopoietic cells from pre-HCT samples obtained from cases that developed t-MDS and controls that did not develop t-MDS after aHCT for lymphoma. We isolated myeloid and lymphoid cell populations from t-MDS cases (n=13) and controls (n=18) using flow cytometry, amplified mtDNA by PCR using specific primers, and sequenced pooled, barcoded amplicons using next generation sequencing on a Illumina Hi-Seq instrument. Sequences were alighted to the revised Cambridge Reference Sequence (rCRS) in the MITOMAP database.We did not identify significant differences in abundance of variations between controls and cases in protein coding genes (control 13.9, case 14.9), hypervariable region (control 7.7, case 6.6) and rRNA/tRNA genes (control 5.7, case 5.6). In addition we did not observe differences in the abundance of variation between cases and controls in individual genes. We also did not detect significant differences in the abundance of SNPs resulting in non-synonymous amino acid changes in lymphoid compared to myeloid populations from both cases (lymphoid 5.0, myeloid 4.7) and controls (lymphoid 5.3, myeloid 4.3). Several new variations in both coding and noncoding regions were identified that were not previously reported in the rCRS database, which were present in greater abundance in myeloid (control 5.3, case 5.3) compared to lymphoid cells (control 1.7, case 2.2). Amongst new variations, the top 5 protein coding genes with the highest number of mutations were found in myeloid cells and included NADH dehydrogenase subunit 2, 4, and 5, and cytochrome c oxidase subunit 1 and 2. We also analyzed the specific mutations that displayed a variation frequency greater than 25% in myeloid control and case samples. Interestingly, the A10398G mutation, in the NADH dehydrogenase subunit 3 (ND3) coding region, associated with metabolic syndrome and increased risk for breast cancer, was found in ∼30% of t-MDS myeloid case samples.In summary our data suggests that there is increased abundance of novel variations in mtDNA in myeloid compared to lymphoid populations. Although several new, previously unreported variations were identified, we did not observe any significant differences in type of lesions, abundance of lesions in coding and non-coding regions, or in individual genes between cases and controls. We conclude that changes in mtDNA sequence are not significantly different between patients that later develop t-MDS after aHCT (cases) compared to controls that do not develop t-MDS. These observations suggest that differences in mtDNA sequence cannot by itself explain the alterations in altered mitochondrial function seen early during the course of development of t-MDS. Disclosures:No relevant conflicts of interest to declare.

Relationship of Myocardial Fibrosis to Left Ventricular and Mitochondrial Function in Nonischemic Dilated Cardiomyopathy—A Comparison of Focal and Interstitial Fibrosis

BackgroundMitochondrial damage is associated with histologic myocardial fibrosis. Late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) can be used to identify focal fibrosis. We examined whether myocardial fibrosis on CMR and collagen volume fraction (CVF) from biopsies correlated with left ventricular (LV) and mitochondrial function in patients with nonischemic dilated cardiomyopathy (DCM). Methods and ResultsFifty-nine DCM patients underwent CMR, cardiac catheterization, and endomyocardial biopsy. Minimum first derivative of LV pressure (LVdP/dtmin) was measured as an index of LV relaxation. Mitochondrial RNA expression was also analyzed. For quantitative analysis of myocardial fibrosis, percentage LGE (%LGE) and CVF were calculated. Patients were divided into 2 groups on the basis of the presence (LGE group; n = 27) or absence (non-LGE group; n = 32) of LGE. Mean CVF and absolute value of LVdP/dtmin were significantly higher and lower, respectively, in the LGE group than in the non-LGE group. Multivariate analysis revealed that %LGE was an independent determinant of LVdP/dtmin. The abundance of mitochondrial enzyme mRNA was significantly lower in the LGE group. ConclusionsNoninvasive CMR imaging is more useful in predicting diastolic dysfunction than invasive histologic assessments. In addition, it might indicate mitochondrial dysfunction in DCM.

Skeletal muscle mitochondrial function: is it quality or quantity that makes the difference in insulin resistance?

), during heightened metabolicdemand (i.e. contraction) there is anessential requirement for rapid andsustained ATP production, a role fulfilledprimarilybymitochondria.Assuch,skeletalmuscle cells are densely populated withthese complex organelles.Withanincreasingprevalenceofinactivityand obesity, type 2 diabetes has become amajor public health concern. Given theircentral role in energy production, it isperhaps not surprising that mitochondrialdysfunction has been implicated inthe aetiology of skeletal muscle insulinresistance, a precursor of frank diabetes.Furthermore,interventionswhichstimulateskeletal muscle mitochondrial biogenesiscan improve insulin sensitivity in obeseand/or insulin resistant individuals. Whileit seems clear that a reduction inskeletal muscle mitochondrial

Habitual Physical Activity in Mitochondrial Disease

PurposeMitochondrial disease is the most common neuromuscular disease and has a profound impact upon daily life, disease and longevity. Exercise therapy has been shown to improve mitochondrial function in patients with mitochondrial disease. However, no information exists about the level of habitual physical activity of people with mitochondrial disease and its relationship with clinical phenotype.MethodsHabitual physical activity, genotype and clinical presentations were assessed in 100 patients with mitochondrial disease. Comparisons were made with a control group individually matched by age, gender and BMI.ResultsPatients with mitochondrial disease had significantly lower levels of physical activity in comparison to matched people without mitochondrial disease (steps/day; 6883±3944 vs. 9924±4088, p = 0.001). 78% of the mitochondrial disease cohort did not achieve 10,000 steps per day and 48%were classified as overweight or obese. Mitochondrial disease was associated with less breaks in sedentary activity (Sedentary to Active Transitions, % per day; 13±0.03 vs. 14±0.03, p = 0.001) and an increase in sedentary bout duration (bout lengths / fraction of total sedentary time; 0.206±0.044 vs. 0.187±0.026, p = 0.001). After adjusting for covariates, higher physical activity was moderately associated with lower clinical disease burden (steps / day; rs = −0.49; 95% CI −0.33, −0.63, P<0.01). There were no systematic differences in physical activity between different genotypes mitochondrial disease.ConclusionsThese results demonstrate for the first time that low levels of physical activity are prominent in mitochondrial disease. Combined with a high prevalence of obesity, physical activity may constitute a significant and potentially modifiable risk factor in mitochondrial disease.

Mitochondrial dysfunction in patients with primary congenital insulin resistance.

Mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes. It has thus been suggested that primary and/or genetic abnormalities in mitochondrial function may lead to accumulation of toxic lipid species in muscle and elsewhere, impairing insulin action on glucose metabolism. Alternatively, however, defects in insulin signaling may be primary events that result in mitochondrial dysfunction, or there may be a bidirectional relationship between these phenomena. To investigate this, we examined mitochondrial function in patients with genetic defects in insulin receptor (INSR) signaling. We found that phosphocreatine recovery after exercise, a measure of skeletal muscle mitochondrial function in vivo, was significantly slowed in patients with INSR mutations compared with that in healthy age-, fitness-, and BMI-matched controls. These findings suggest that defective insulin signaling may promote mitochondrial dysfunction. Furthermore, consistent with previous studies of mouse models of mitochondrial dysfunction, basal and sleeping metabolic rates were both significantly increased in genetically insulin-resistant patients, perhaps because mitochondrial dysfunction necessitates increased nutrient oxidation in order to maintain cellular energy levels.

Opposite effects of pioglitazone and rosiglitazone on mitochondrial respiration in skeletal muscle of patients with type 2 diabetes

Skeletal muscle insulin resistance has been linked to mitochondrial dysfunction. We examined how improvements in muscular insulin sensitivity following rosiglitazone (ROSI) or pioglitazone (PIO) treatment would affect muscle mitochondrial function in patients with type 2 diabetes mellitus (T2DM). Muscle biopsies were obtained from 21 patients with T2DM before and after 12 weeks on either ROSI (4 mg once daily) [n = 12; age, 59.2 +/- 2.2 years; body mass index (BMI), 29.6 +/- 0.7 kg/m(2)] or PIO (30 mg once daily) (n = 9; age, 56.3 +/- 2.4 years; BMI, 29.5 +/- 1.5 kg/m(2)). An age- and BMI-matched control group was also included (n = 8; age, 61.8 +/- 2.3 years; BMI, 28.4 +/- 0.6 kg/m(2)). Insulin sensitivity, citrate synthase- and beta-hydroxyacyl-CoA-dehydrogenase (HAD) activity, intramuscular triglyceride (IMTG) and protein content of complexes I-IV were measured, while mitochondrial respiration per milligram muscle was measured in saponin-treated skinned muscle fibres using high-resolution respirometry. Mitochondrial respiration per milligram muscle was lower in T2DM compared to controls at baseline and decreased during ROSI treatment but increased during PIO treatment. Citrate synthase activity and average protein content of complexes I-IV were unchanged in the ROSI group, but protein content of complexes II and III increased during PIO treatment. Insulin sensitivity improved in all patients, but IMTG levels were unchanged. We show opposite effects of ROSI and PIO on mitochondrial respiration, and also show that insulin sensitivity can be improved independently of changes in mitochondrial respiration. We confirm that mitochondrial respiration is reduced in T2DM compared to age- and BMI-matched control subjects.

Muscle Mitochondrial Function in Patients with Type 2 Diabetes Mellitus and Peripheral Arterial Disease: Implications in Vascular Surgery

(1) To review the available information on mitochondrial function in type 2 diabetes mellitus (T2DM) and peripheral arterial disease (PAD) obtained by non-invasive phosphorus magnetic resonance spectroscopy ((31)PMRS), near-infrared spectroscopy (NIRS) in vivo and respirometry on mitochondria isolated from muscle biopsies in vitro (2) to evaluate the usefulness of such data in the diagnosis, treatment and prognosis of these patients. Review. PubMed (http://www.ncbi.nlm.nih.gov/PubMed) and manual literature search. Fifty-three articles were retrieved, which included (31)PMRS, 15, NIRS, 11, Combined, 1 and Respirometry, 2 and background literature, 24. Muscle mitochondrial function is impaired in both T2DM and PAD patients, but differently. Patients suffering from both pathological conditions will display more serious impairment of the mitochondrial function. Mitochondrial function and the degree of ischaemic disease as evaluated by (31)PMRS and NIRS are well correlated. The NIRS technique appears to determine the degree of PAD better than (31)PMRS. It is argued that systematic testing of mitochondrial function may be a useful prognostic tool with PAD and T2DM, but clinical studies are needed.

Frequency of Mitochondrial Defects in Patients With Chronic Intestinal Pseudo-Obstruction

Chronic intestinal pseudo-obstruction (CIPO) is a rare disorder caused by intestinal dysmotility and characterized by chronic symptoms suggesting bowel obstruction in the absence of fixed, occluding lesions. CIPO has been associated with primary defects of the mitochondrial oxidative phosphorylation pathway, although the frequency of mitochondrial disorders in patients with CIPO is unknown. This study evaluates mitochondrial function in patients with CIPO. A retrospective study was performed of data collected from 80 CIPO patients at a tertiary centre over a 25-year period. Mitochondrial disorders were detected by analysis of serum lactate and thymidine phosphorylase activities, brain magnetic resonance images, and muscle biopsies. Genes encoding thymidine phosphorylase, mitochondrial DNA tRNA(leu(UUR)) or tRNA(lys), and DNA polymerase-gamma were analyzed for mutations. Mitochondrial defects were identified in 15 patients (10 women; median age at diagnosis 32 years), representing 19% of the study cohort. All 15 patients had extra-digestive symptoms, 5 had mutations in the thymidine phosphorylase gene, 2 had mutations in tRNA(leu(UUR)), and 5 had mutations in the DNA polymerase-gamma gene. No genetic defect was detected in 3 of the patients with mitochondrial disorders. Patients with mitochondrial CIPO differed from patients without mitochondrial defects in their very severe nutritional status (frequent and long-term requirement for parenteral nutrition) and poor prognosis (frequent digestive and neurologic complications that led to a high incidence of premature death). Mitochondrial disorders seem to be an important cause of CIPO. Patients with CIPO, especially severe cases with associated neurologic symptoms, should be tested for mitochondrial defects.

Effect of Hyperglycemia on Mitochondrial Respiration in Type 2 Diabetes

Skeletal muscle mitochondrial content is reduced in type 2 diabetes mellitus (T2DM). Whether hyperglycemia inhibits mitochondrial biogenesis and/or function is unknown. This study examined the effect of different levels of glycemia on skeletal muscle mitochondrial function in patients with T2DM. Eleven patients with T2DM [9 males, 2 females; age, 52.8 +/- 2.5 yr (mean +/- se); body mass index, 30.2 +/- 1.1 kg/m(2)] in poor glycemic control were treated with insulin aspart and NPH insulin for a median period of 46 d (range, 31-59). Mitochondrial respiration and citrate synthase activity (a marker of mitochondrial content) were measured before and after treatment. Eleven healthy subjects (age, 53.3 +/- 2.7 yr; body mass index, 30.6 +/- 1.1 kg/m(2)) were included as controls. Hemoglobin A1c (9.1 +/- 0.5 to 7.5 +/- 0.3%; P < 0.001) and fasting plasma glucose (12.7 +/- 1.1 to 6.5 +/- 0.3 mmol/liter; P < 0.001) were reduced after treatment. Mitochondrial respiration per milligram muscle was lower in T2DM compared to controls [substrates for complex I, 24% lower (P < 0.05); substrates for complex I+II, 17% lower (P < 0.05)]. Mitochondrial respiration and citrate synthase activity did not differ before and after improvements in glycemic control, but mitochondrial respiration correlated with fasting plasma glucose before (r(2) = 0.53; P < 0.05) but not after treatment [r(2) = 0.0024; not significant (NS)]. Mitochondrial respiration normalized to mitochondrial content did not differ between control subjects and patients with T2DM. Mitochondrial respiration and content was not improved after significant improvements in glycemic control. However, severe hyperglycemia inhibited respiration reversibly, but moderate hyperglycemia and mitochondrial function were not correlated.

Liver Mitochondrial Function in Familial Amyloidotic Polyneuropathy

The objective of the present study was to analyze hepatic mitochondrial function in patients with familial amyloidotic polyneuropathy (FAP) undergoing cadaveric donor orthotopic liver transplantation. From February 2005 to May 2007, eight patients with FAP, ranging in age from 34 to 41 years and with Model for End-Stage Liver Disease scores ranging from 24 to 29. Underwent orthotopic transplantation using a liver from a deceased donor by the piggyback method. Immediately before beginning the recipient hepatectomy in a patient with FAP, a biopsy was obtained for analysis of mitochondrial function (FAP group). The control group consisted of 15 patients undergoing hepatic surgery to treat small tumors of the liver. Mitochondrial respiration was determined on the basis of oxygen consumption by energized mitochondria using a polarographic method. The membrane potential of the mitochondria was determined spectrofluorometrically. Data were analyzed statistically by the Mann-Whitney test, with the level of significance set at 5%. State 3 and 4 values, respiratory control ratio, and membrane potential were 47 ± 8 versus 28 ± 10 natoms O/min/mg protein ( P < .05); 14 ± 3 vs 17 ± 7 nat.O/min/mg.prot.mit. ( P > .05); 3.6 ± .5 vs 1.7 ± 0.7 ( P < .05); and 135 ± 5.2 vs 135 ± 6 mV ( P > .05) for control versus FAP patients, respectively, demonstrating a decreased energy status of the liver in FAP.

Oxidation –reduction states of NADH in vivo: From animals to clinical use

Mitochondrial dysfunction is part of many pathological states in patients, such as sepsis or stroke. Presently, the monitoring of mitochondrial function in patients is extremely rare, even though NADH redox state is routinely measured in experimental animals. In this article, we describe the scientific backgrounds and practical use of mitochondrial NADH fluorescence measurement that was applied to patients in the past few years. In addition to NADH, we optically measured the microcirculatory blood flow and volume, as well as HbO 2 oxygenation, from the same tissue area. The four detected parameters provide real time data on tissue viability, which is critical for patients monitoring.

Impairment of muscle mitochondrial function in patients with prior acromegaly

Impairment of muscle mitochondrial function in patients with prior acromegaly

A novel clinical indicator using Tc-99m sestamibi for evaluating cardiac mitochondrial function in patients with cardiomyopathies

Technetium 99m sestamibi (MIBI) is a technetium-labeled myocardial perfusion agent that is taken up by the myocardial cell in proportion to myocardial regional blood flow and remains fixed in the myocardial cell over a long period of time. Previous studies have suggested that MIBI shows very slow myocardial clearance after its initial uptake in an animal model, which is related to mitochondrial function. This study was designed to test the hypothesis that MIBI washout can be used to evaluate the severity of congestive heart failure in comparison to other clinical parameters in patients with cardiomyopathies. After administration of MIBI, 61 patients with nonischemic congestive heart failure (49 with dilated cardiomyopathy and 12 with other cardiomyopathies) and 7 normal control subjects were examined by electrocardiography-gated myocardial perfusion single photon emission computed tomography and planar data acquisition in the early and delayed phases (interval of 3 hours). Myocardial MIBI washout rates were calculated from the early and delayed planar images. Left ventricular function (systolic and diastolic) was analyzed by use of QGS data. Plasma levels of B-type natriuretic peptide and iodine 123 metaiodobenzylguanidine (MIBG) parameters were also measured. Patients were followed up for a mean of 12 months (range, 1-19 months). As the severity of the New York Heart Association (NYHA) functional class advanced, the washout rate of MIBI increased (21.6% +/- 2.4% in those with NYHA class I [n = 23], 28% +/- 4% in those with NYHA class II [n = 27], and 35% +/- 5% in those with NYHA class III [n = 10]; P < .05, analysis of variance). The washout rate of MIBI was positively correlated with the level of B-type natriuretic peptide (r = 0.31, P < .05), end-diastolic volume (r = 0.396, P < .01), and end-systolic volume (r = 0.496, P < .01) and was negatively correlated with left ventricular ejection fraction (r = 0.523, P < .01), peak filling rate (r = 0.444, P < .01), and first-third ejection fraction (r = 0.414, P < .01). The parameters of MIBG scintigraphy were calculated as the heart-mediastinum count ratio (1.9 +/- 3) and washout rate (38% +/- 4%). We found a significant relationship between the washout rate of MIBI and the heart-mediastinum count ratio of MIBG (r = 0.51, P < .01). Patients with a higher washout rate of MIBI had a higher cardiac event rate (> or =28%) than those with a lower washout rate (<28%) (P < .05). The myocardial washout rate of MIBI is thought to be a novel marker for the diagnosis of myocardial damage or dysfunction, providing prognostic information in patients with congestive heart failure.

In vivo assessment of skeletal muscle mitochondrial function in patients on long-term home parenteral nutrition for chronic intestinal failure

In vivo assessment of skeletal muscle mitochondrial function in patients on long-term home parenteral nutrition for chronic intestinal failure

Respiratory-chain enzyme activities in isolated mitochondria of lymphocytes from patients withParkinson′s disease: Preliminary study

Evidence suggests that mitochondrial dysfunction stimulates the production of reactive oxygen species (ROS) that promote neural cell death in stroke and in Parkinson's disease. The sites of mitochondrial ROS production are not established but are generally believed to be located within the electron transport chain. We studied the mitochondrial respiratory chain enzymes function from human circulating lymphocytes. Open study. Forty patients with Parkinson's disease (PD) with 30 age-matched control subjects were selected in this study. The patients had received no treatment before the study was conducted. The data from patients and controls were compared using two-tailed student's t-test and values were expressed as means +/- standard deviation (SD). Respiratory complex I + III and IV activities were significantly lower (P < 0.001) in patients than in control subjects. The use of lymphocytes for investigating the respiratory chain enzymes provides an easy, noninvasive method to assess mitochondrial function in patients with PD. Furthermore, our study supports the hypothesis that a biochemical defect in the respiratory chain may be involved in the pathogenesis of PD.

Aerobic exercise and muscle metabolism in patients with mitochondrial myopathy

Exercise therapy improves mitochondrial function in patients with mitochondrial myopathy (MM). We undertook this study to determine the metabolic abnormalities that are improved by exercise therapy. This study identified metabolic pathology using (31)P-magnetic resonance spectroscopy and magnetic resonance imaging (MRI) in a group of patients with MM compared to a control group matched for age, gender, and physical activity. We also observed the effect of exercise therapy for 12 weeks on muscle metabolism and physical function in the MM group. During muscle activity, there was impaired responsiveness of the mitochondria to changes in cytosolic adenosine diphosphate concentration, increased dependence on anaerobic energy pathways, and an adaptive increase in proton efflux in patients with MM. Following exercise therapy, mitochondrial function and muscle mass improved without any change in proton efflux rate. These metabolic findings were accompanied by improvements in functional ability. We conclude that there are significant metabolic differences between patients with MM and a control population, independent of age, gender, and physical activity. Exercise therapy can assist in improving mitochondrial function in MM patients.

How is Mitochondrial Biogenesis Affected in Mitochondrial Disease?

Mitochondrial biogenesis occurs when the tissue energy demand is chronically increased to stress the ATP producing capacity of the preexisting mitochondria. In muscle, endurance training is a metabolic stress that is capable of inducing mitochondrial biogenesis, the consequence of which is improved performance during exercise. Expansion of the mitochondrial volume requires the coordinated response of the nuclear and mitochondrial genomes. During acute exercise, the initial signaling events are the perturbations in ATP turnover and calcium (Ca) concentrations caused by the contractile process. These alterations activate signal transduction pathways which target transcription factors involved in gene expression. Nuclear gene products are then posttranslationally imported into mitochondria. One of these, Tfam, is important for the regulation of mitochondrial DNA (mtDNA) gene expression. In muscle, a broad range of mitochondrial-specific diseases due to mutations in nuclear DNA or mtDNA exist, termed mitochondrial myopathies. These mutations result in dysfunctional mitochondrial assembly which ultimately leads to reduced ATP production. Mitochondrial myopathy patients exhibit a variety of compensatory responses which attempt to reconcile this energy deficiency, but the extent and the type of compensatory adaptations are disease-specific. Understanding the role of exercise in mediating these compensatory responses leading to mitochondrial biogenesis could help us in prescribing exercise designed to improve mitochondrial function in patients with mitochondrial myopathies. In addition, numerous other diseases (e.g., neurological disorders, cancer, diabetes, and cardiomyopathies), as well as the aging process, have etiologies or consequences attributed, in part, to mitochondrial dysfunction. Thus, insight gained by investigating the steps involved in exercise-induced mitochondrial biogenesis may help us to understand the underlying basis of these other disease states.

A New Noninvasive Test to Detect Mitochondrial Dysfunction of Skeletal Muscles in Progressive Supranuclear Palsy

We present usage of technetium-99m methoxyisobutyl isonitrile (99mTc-sestamibi) single photon emission computed tomography (SPECT) as a novel noninvasive method to evaluate muscular mitochondrial function in patients with progressive supranuclear palsy (PSP). 99mTc-sestamibi SPECT revealed a statistically significant decrease in radionucleotide uptake in the quadriceps in PSP patients as compared with other neurodegenerative parkinsonism (P < 0.05) or control group (P < 0.05). This study demonstrates a remarkable deficit of skeletal muscle bioenergetics in patients with PSP. Our findings suggest a distinctive role of mitochondrial dysfunction in the pathogenesis of PSP. Furthermore, 99mTc-sestamibi SPECT provides a relatively simple, inexpensive, and noninvasive modality in further assessment of mitochondrial function and bioenergetic features in various muscular disorders.

Treatment with reduced nicotinamide adenine dinucleotide (NADH) improves water maze performance in old Wistar rats

Age-associated cognitive impairment and related neurodegenerative disorders are an increasing major public health problem. Nicotinamide adenine dinucleotide (NADH), a co-substrate for energy transfer in the mitochondrial respiratory chain, is speculated to induce positive effects in some of these diseases. Studies showed diminished mitochondrial function in patients with M. Alzheimer. In a preliminary clinical trial NADH given peripherally improved cognitive function in Alzheimer disease. Previous own experiments revealed an increased NADH level in the rat brain following peripheral application of NADH (10–100 mg/kg, i.p.+ i.v.). Therefore, we wanted to know, whether or not NADH has an effect on cognitive function in animals. We analysed the effect of repeated i.p. injection of NADH on the performance of 3-month-old and 22-month-old Wistar rats in the Morris water maze and in the rota-rod test of motor coordination. The rats were injected for 10 days once daily with the doses of NADH used in the bioavailability study (10–100 mg/kg) or vehicle 20 min before the behavioural tests. The repeated administration of NADH improved the performance of old rats in the acquisition phase (place version) and the spatial probe of the Morris water maze compared to vehicle-treated controls. The effect of NADH on learning-related processes is supported by the lack of effects on motor performance on the rota-rod. In summary, our results suggest cognitive enhancing properties of NADH in learning impaired old rats.

Abnormal Platelet Mitochondrial Function in Patients Affected by Migraine With and Without Aura

To investigate energy metabolism in migraine, we determined platelet mitochondrial enzyme activities in 40 patients with migraine with aura and in 40 patients with migraine without aura during attack-free intervals and in 24 healthy control subjects. NADH-dehydrogenase, citrate synthase and cytochrome-c-oxidase activities in both patient groups were significantly lower than in controls (p < 0.01), while NADH-cytochrome-c-reductase activity was reduced only in migraine with aura (p < 0.01). No alteration in succinate-dehydrogenase was observed. Monoamine-oxidase activity differed between sexes (p < 0.05) but within each sex group no difference was observed between patients and controls. We hypothesize that the defect in mitochondrial enzymes observed indicates a systemic impairment of mitochondrial function in migraine patients.