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Cardiac failure is associated with diminished activation of the transcription factor cyclic nucleotide regulatory element binding-protein (CREB), and heart-specific expression of a phosphorylation-deficient CREB mutant in transgenic mice [dominant negative CREB (dnCREB) mice] recapitulates the contractile phenotypes of cardiac failure (Fentzke RC, Korcarz CE, Lang RM, Lin H, Leiden JM. Dilated cardiomyopathy in transgenic mice expressing a dominant-negative CREB transcription factor in the heart. J Clin Invest 101: 2415-2426, 1998). In the present study, we demonstrated significantly elevated mortality and contractile dysfunction in female compared with male dnCREB mice. Female dnCREB mice demonstrated a 21-wk survival of only 17% compared with 67% in males (P < 0.05) and exclusively manifest decreased cardiac peroxisome proliferator-activated receptor-[gamma] coactivator-1[alpha] and estrogen-related receptor-[alpha] content, suggesting sex-related effects on cardiac mitochondrial function. Hearts from 4-wk-old dnCREB mice of both sexes demonstrated diminished mitochondrial respiratory capacity compared with nontransgenic controls. However, by 12 wk of age, there was a significant decrease in mitochondrial density (citrate synthase activity) and deterioration of mitochondrial structure, as demonstrated by transmission electron microscopy, in female dnCREB mice, which were not found in male transgenic littermates. Subsarcolemmal mitochondria isolated from hearts of female, but not male, dnCREB mice demonstrated increased ROS accompanied by decreases in the expression/activity of the mitochondrial antioxidants MnSOD and glutathione peroxidase. These results demonstrate that heart-specific dnCREB expression results in mitochondrial respiratory dysfunction in both sexes; however, increased oxidant burden, reduced antioxidant expression, and disrupted mitochondrial structure are exacerbated by the female sex, preceding and contributing to the greater contractile morbidity and mortality. These results provide further support for the role of the CREB transcription factor in regulating mitochondrial integrity and identify a critical pathway that may contribute to sex differences in heart failure. oxidative stress; mitochondria; cyclic nucleotide regulatory element binding-protein; apoptosis doi:10.1152/ajpheart.00394.2010.

Mitochondrial dysfunction may be a long-term consequence of a poor nutritional environment during early life. Our aim was to investigate whether a maternal low-protein (LP) diet may program mitochondrial dysfunction in islets of adult progeny before glucose intolerance ensues. To address this, pregnant Wistar rats were fed isocaloric diets containing either 20% protein (control) or 8% protein (LP diet) throughout gestation. From birth, offspring received the control diet. The mitochondrial function was analyzed in islets of 3-mo-old offspring. Related to their basal insulin release, cultured islets from both male and female LP offspring presented a lower response to glucose challenge and a blunted ATP production compared with control offspring. The expression of malate dehydrogenase as well as the subunit 6 of the ATP synthase encoded by mitochondrial genome (mtDNA) was lower in these islets, reducing the capacity of ATP production through the Krebs cycle and oxidative phosphorylation. However, mtDNA content was unchanged in LP islets compared with control. Several consequences of protein restriction during fetal life were more marked in male offspring. Only LP males showed an increased reactive oxygen species production associated with a higher expression of mitochondrial subunits of the electron transport chain NADH-ubiquinone oxireductase subunit 4L, an overexpression of peroxisome proliferator-activated receptor-[gamma] and uncoupling protein-2, and a strongly reduced beta-cell mass. In conclusion, mitochondrial function is clearly altered in islets from LP adult offspring in a sex-specific manner. That may provide a cellular explanation for the earlier development of glucose intolerance in male than in female offspring of dams fed an LP diet. developmental programming; malnutrition; metabolic syndrome; insulin secretion doi: 10.1152/ajpregu.00280.2009.

A study was conducted to examine five complex I-deficient patients with mutations in NDUFAF3 gene. Findings revealed a severe isolated complex I deficiency in all patients.

The article presents the symptoms and effects of the complex I deficiency that is caused by the mutation of the putative complex I assembly factor C20orf7, which is known to cause the lethal neonatal mitochondrial disease. C20orf7 is shown to be extremely crucial for the assembly of complex I.

The development of an infantile mitochondrial encephalomyopathy due to developmental delay, hemiplegia and low cytochrome c oxidase (COX) activity in the skeletal muscle is discussed. The nonsense mutation of the fas activated serine-threonine kinase domain 2 (FASTKD2) protein is shown to play a very important role in the mitochondrial apoptosis.

Aging is the most important risk factor for common neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Aging in the central nervous system has been associated with elevated mutation load in mitochondrial DNA, defects in mitochondrial respiration and increased oxidative damage. These observations support a 'vicious cycle' theory which states that there is a feedback mechanism connecting these events in aging and age-associated neurodegeneration. Despite being an extremely attractive hypothesis, the bulk of the evidence supporting the mitochondrial vicious cycle model comes from pharmacological experiments in which the modes of mitochondrial enzyme inhibition are far from those observed in real life. Furthermore, recent in vivo evidence does not support this model. In this review, we focus on the relationship among the components of the putative vicious cycle, with particular emphasis on the role of mitochondrial defects on oxidative stress.

Despite the fact that important genetic diseases are caused by mutant mitochondrial ribosomes, the molecular mechanisms by which such ribosomes result in a clinical phenotype remain largely unknown. The absence of experimental models for mitochondrial diseases has also prevented the rational search for therapeutic interventions. Here, we report on the construction of bacterial hybrid ribosomes that contain various versions of the mitochondrial decoding region of ribosomal RNA. We show that the pathogenic mutations A1555G and C1494T decrease the accuracy of translation and render the ribosomal decoding site hypersusceptible to aminoglycoside antibiotics. This finding suggests misreading of the genetic code as an important molecular mechanism in disease pathogenesis. decoding | mitochondria | mutant rRNA | ribosomes | disease

Mitochondrial dysfunction in skeletal muscle has been implicated in the development of type 2 diabetes. However, whether these changes are a cause or a consequence of insulin resistance is not clear. We investigated the structure and function of muscle mitochondria during the development of insulin resistance and progression to diabetes in mice fed a high-fat, high-sucrose diet. Although 1 month of high-fat, high-sucrose diet feeding was sufficient to induce glucose intolerance, mice showed no evidence of mitochondrial dysfunction at this stage. However, an extended diet intervention induced a diabetic state in which we observed altered mitochondrial biogenesis, structure, and function in muscle tissue. We assessed the role of oxidative stress in the development of these mitochondrial abnormalities and found that diet-induced diabetic mice had an increase in ROS production in skeletal muscle. In addition, ROS production was associated with mitochondrial alterations in the muscle of hyperglycemic streptozotocin-treated mice, and normalization of glycemia or antioxidant treatment decreased muscle ROS production and restored mitochondrial integrity. Glucose- or lipid-induced ROS production resulted in mitochondrial alterations in muscle cells in vitro, and these effects were blocked by antioxidant treatment. These data suggest that mitochondrial alterations do not precede the onset of insulin resistance and result from increased ROS production in muscle in diet-induced diabetic mice., Introduction The prevalence of type 2 diabetes increases dramatically in modern societies, in part because of ample food supplies and a sedentary lifestyle. Excess dietary fat and sugar plays a [...]

The proportions of mutant and wild-type mtDNA are crucial in determining the severity of mitochondrial diseases. It has been generally considered that deletion-mutant mtDNA has replication advantages and accumulates with time. Here, we examine the tissue-by-tissue proportions of mutant mtDNA with a 4696-bp deletion ([DELTA]mtDNA) and wild-type mtDNA in mitochondrial disease model mice (mito-mice). Comparison of the proportions of [DELTA]mtDNA in each tissue at various ages showed that the rate of accumulation of [DELTA]mtDNA differed among tissues. The heart, skeletal muscles, kidney, liver, testis, and ovary showed increases in the proportion of [DELTA]mtDNA with age, but the pancreas, spleen, brain, and blood showed only a slight or no increase in proportion. In contrast to the somatic tissues, however, the germ cells of female mito-mice and resultant offspring showed a strong decrease in [DELTA]mtDNA with maternal age. The decrease was so acute that some offspring showed complete disappearance of [DELTA]mtDNA, even though their elder brothers and sisters had high proportions of [DELTA]mtDNA. Female germ cells have a machinery that prevents the inheritence of defective mtDNA to the following generation since germ cells are kept for a long time until they are ovulated.

Kim HK, Park WS, Kang SH, Warda M, Kim N, Ko J-H, Prince AE, Han J. Mitochondrial alterations in human gastric carcinoma cell line. Am J Physiol Cell Physiol 293: C761-C771, 2007. First published May 30, 2007; doi: 10.1152/ajpcell.00043.2007.--We compared mitochondrial function, morphology, and proteome in the rat normal gastric cell line RGM-1 and the human gastric cancer cell line AGS. Total numbers and cross-sectional sizes of mitochondria were smaller in AGS cells. Mitochondria in AGS cells were deformed and consumed less oxygen. Confocal microscopy indicated that the mitochondrial inner membrane potential was hyperpolarized and the mitochondrial [Ca.sup.24] concentration was elevated in AGS cells. Interestingly, two-dimensional electrophoresis proteomics on the mitochondria-enriched fraction revealed high expression of four mitochondrial proteins in AGS cells: ubiquinol-cytochrome c reductase, mitochondrial short-chain enoyl-coenzyme A hydratase-1, heat shock protein 60, and mitochondria elongation factor Tu. The results provide clues as to the mechanism of the mitochondrial changes in cancer at the protein level and may serve as potential cancer biomarkers in mitochondria. two-dimensional gel electrophoresis proteomics; biomarker; cancer

Mitochondrial dysfunction is involved in many neurodegenerative disorders in humans. Here we report mutations in a gene (designated levy) that codes for subunit Via of cytochrome c oxidase (COX). The mutations were identified by the phenotype of temperature-induced paralysis and showed the additional phenotypes of decreased COX activity, age-dependent bang-induced paralysis, progressive neurodegeneration, and reduced life span. Germ-line transformation using the [levy.sup.+] gene rescued the mutant flies from all phenotypes including neurodegeneration. The data from levy mutants reveal a COX-mediated pathway in Drosophila, disruption of which leads to mitochondrial encephalomyopathic effects including neurodegeneration, motor dysfnnction, and premature death. The data present the first case of a mutation in a nuclear-encoded structural subunit of COX that causes mitochondrial encephalomyopathy rather than lethality, whereas several previous attempts to identify such mutations have not been successful. The levy mutants provide a genetic model to understand the mechanisms underlying COX-mediated mitochondrial encephalomyopathies and to explore possible therapeutic interventions.

We have recently demonstrated that mitochondrial respiratory dysfunction and mitochondrial permeability transition pore opening during postinfarction remodeling are prevented by the [Na.sup.+]/[H.sup.+] exchange-1 (NHE-1)-specific inhibitor EMD-87580 (EMD). One of the mechanisms underlying the beneficial effect of NHE-1 inhibition on mitochondria could result from the drug's ability to regulate transcriptional factors responsible for mitochondrial function. In the present study, the effect of EMD on the expression of nuclear factors involved in mitochondrial biogenesis and expression of nuclear (COXNUCSUB IV) and mitochondrial (COXMITSUB I) encoded cytochrome c oxidase subunits has been studied in rat hearts subjected to either 12 or 18 wk of coronary artery ligation (CAL). Remodeling induced an increase in expression of the hypertrophic marker gene atrial natriuretic peptide, especially 12 wk after CAL. The mRNA level of the peroxisome proliferator-activated receptor-[gamma] coactivator-1[alpha] and its downstream factors, including nuclear respiratory factor 1 and 2, mitochondrial transcription factor A, COXNUCSUB IV, and COXMITSUB I, were significantly reduced in hearts both 12 and 18 wk after ligation compared with sham-operated hearts. Dietary EMD provided immediately after ligation attenuated downregulation of mitochondrial transcription factors with a parallel decrease of hypertrophic marker gene expression. Regression analysis demonstrated a strong positive correlation between the transcription factors and mitochondrial respiratory function. Thus our study shows that the downregulation of mitochondrial transcription factors induced by postinfarction remodeling can be significantly attenuated by NHE-1 inhibition with a further improvement of mitochondrial function in these hearts. cardiac remodeling; mitochondria; sodium/hydrogen exchanger-1 inhibition; transcription factors

The genetics of mitochondrial diseases is reviewed. Topics include mitochondrial genetics, metabolic pathways in mitochondria, mitochondrial DNA and the mitochondrial respiratory chain, respiratory chain disorders caused by defects in mitochondrial DNA, mutations of mitochondrial DNA that cause disease, respiratory chain disorders caused by defects in nuclear DNA, and therapeutic approaches. Mitochondria are structures inside cells that create energy from food.

Byline: Monica Sciacco (5), Alessandro Prelle (5), Giacomo P. Comi (5), Laura Napoli (5), Alessandro Battistel (5), Nereo Bresolin (5), Lucia Tancredi (5), Costanza Lamperti (5), Adreina Bordoni (5), Gigliola Fagiolari (5), Patrizia Ciscato (5), Luca Chiveri (5), Maria Paola Perini (5), Francesco Fortunato (5), Laura Adobbati (1), Stefano Messina (5), Antonio Toscano (2), Filippo Martinelli-Boneschi (4), Alex Papadimitriou (3), Guglielmo Scarlato (5), Maurizio Moggio (5) Keywords: Key words Neuromuscular disease; Clinical evaluation; Neurogenetics; Mitochondrial Abstract: Mitochondrial disorders are human genetic diseases with extremely variable clinical and genetic features. To better define them, we made a genotype-phenotype correlation in a series of 207 affected patients, and we examined most of them with six laboratory examinations (serum CK and basal lactate levels, EMG, cardiac and EEG studies, neuroradiology). We found that, depending on the genetic abnormality, hyperckemia occurs most often with either chronic progressive external ophthalmoplegia (CPEO) and ptosis or with limb weakness. Myopathic EMGs are more common than limb weakness, except in patients with A8344G mutations. Peripheral neuropathy, when present, is always axonal. About 80 % of patients with A3243G and A8344G mutations have high basal lactate levels, whereas pure CPEO is never associated with increased lactate levels. Cardiac abnormalities mostly consist of conduction defectsAbnormalities on CT or MRI of the brain are relatively common in A3243G mutations independently of the clinical phenotype. Patients with multiple mtDNA deletions are somehow 'protected' against the development of abnormalities with any of the tests. We conclude that, despite the phenotypic heterogeneity of mitochondrial disorders, correlation of clinical features and laboratory findings may give the clinician important clues to the genetic defect, allowing earlier diagnosis and counselling. Author Affiliation: (1) Dipartimento di Neurologia, Ospedale Valduce, Como, Italy, IT (2) Clinica Neurologica II, Universita di Messina, Italy, IT (3) Department of Neurology, Red Cross Hospital, Athens, Greece, GR (4) Department of Neurology, Ospedale San Raffaele, Italy, IT (5) Centro Dino Ferrari, Istituto di Clinica Neurologica, University of Milan, Ospedale Maggiore IRCCS, Via F. Sforza 35, 20122 Milan, Italy, Tel.: 0039-02-55033801, Fax: 0039-02-55190392, e-mail: scspneur@mailserver.unimi.it, IT Article note: Received: 8 December 2000 / Received in revised form: 18 February 2001 / Accepted: 13 March 2001

Byline: Y. S. Lee (1), Hui Kim Yap (2), Bruce A Barshop (3), Yoke Sun Lee (4), Sinniah Rajalingam (4), Kah Yin Loke (2) Keywords: Keywords Mitochondrial disorder; Proximal renal tubular dysfunction; Hypoparathyroidism Abstract: We report a rare presentation of mitochondrial disorder in a child with recurrent carpopedal spasms due to hypocalcemia and hypomagnesemia, secondary to renal proximal tubulopathy and possible hypoparathyroidism. At least two mutant mitochondrial DNA species were identified, and abnormal mitochondria were found in the muscle and renal biopsy specimens. The case illustrates the spectrum and diversity of mitochondrial presentations, arising because of heteroplasmy of mutations and the type of organs affected. Author Affiliation: (1) National University of Singapore, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074. paeleeys@nus.edu.sg, SG (2) Department of Pediatrics, National University of Singapore, Singapore, SG (3) Department of Pediatrics, University of California, San Diego, California, USA, US (4) Department of Pathology, National University of Singapore, Singapore, SG Article note: Received: 31 October 2000 / Revised: 16 April 2001 / Accepted: 17 April 2001

The article discusses various nuclear gene mutations that lead to changes in the mitochondrial DNA (mtDNA) and causes several mitochondrial diseases in humans. These genes act as the proteins of mtDNA replication or provide the required precursors for the replication.

Aug 21 People's ability to convert folic acid from fortified foods and vitamin supplements into its active form happens more slowly and varies more widely than previously thought, a study [...]