Mitochondrial Oxidative Phosphorylation (mitochondrial + oxidative_phosphorylation)

Distribution by Scientific Domains

Selected Abstracts

The neurologic manifestations of mitochondrial disease

Sumit Parikh
Abstract The nervous system contains some of the body's most metabolically demanding cells that are highly dependent on ATP produced via mitochondrial oxidative phosphorylation. Thus, the neurological system is consistently involved in patients with mitochondrial disease. Symptoms differ depending on the part of the nervous system affected. Although almost any neurological symptom can be due to mitochondrial disease, there are select symptoms that are more suggestive of a mitochondrial problem. Certain symptoms that have become sine qua non with underlying mitochondrial cytopathies can serve as diagnostic "red-flags." Here, the typical and atypical presentations of mitochondrial disease in the nervous system are reviewed, focusing on "red flag" neurological symptoms as well as associated symptoms that can occur in, but are not specific to, mitochondrial disease. The multitudes of mitochondrial syndromes are not reviewed in-depth, though a select few are discussed in some detail. 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:120,128. [source]

The Effects of Ecstasy (MDMA) on Rat Liver Bioenergetics

Daniel E. Rusyniak MD
Abstract Objectives: Use of the drug ecstasy (3,4-methylenedioxymethamphetamine [MDMA]) can result in life-threatening hyperthermia. Agents that uncouple mitochondrial oxidative phosphorylation are known to cause severe hyperthermia. In the present study, the authors tested the hypothesis that MDMA directly uncouples oxidative phosphorylation in rat liver mitochondria. Methods: Effects on mitochondrial bioenergetics were assessed both in vitro and ex vivo. In vitro studies consisted of measuring the effects of MDMA (0.1,5.0 mmol/L) on states of respiration in isolated rat liver mitochondria and on mitochondrial membrane potential in a rat liver cell line. In ex vivo studies, mitochondrial rates of respiration were measured in the livers of rats one hour after treatment with MDMA (40 mg/kg subcutaneously). Results: With the in vitro mitochondrial preparations, only concentrations of 5 mmol/L MDMA showed evidence of uncoupling with a slight increase in state 4 respiration and a corresponding decrease in the respiratory control index. MDMA (0.1,5.0 mmol/L) failed to decrease the mitochondrial membrane potential in 3,3-dihexyloxacarbocyanide iodide,stained WB-344 cells after either one or 24 hours of incubation. Ex vivo rates of respiration obtained from the livers of rats one hour after treatment with MDMA (40 mg/kg subcutaneously) showed no evidence of mitochondrial uncoupling. Conclusions: These data suggest that while high concentrations of MDMA have some mild uncoupling effects in isolated mitochondria, these effects do not translate to cell culture or ex vivo studies in treated animals. These data do not support the view that the hyperthermia induced by MDMA is from a direct effect on mitochondrial oxidative phosphorylation. [source]

Control of p70 ribosomal protein S6 kinase and acetyl-CoA carboxylase by AMP-activated protein kinase and protein phosphatases in isolated hepatocytes

FEBS JOURNAL, Issue 15 2002
Ulrike Krause
Certain amino acids, like glutamine and leucine, induce an anabolic response in liver. They activate p70 ribosomal protein S6 kinase (p70S6K) and acetyl-CoA carboxylase (ACC) involved in protein and fatty acids synthesis, respectively. In contrast, the AMP-activated protein kinase (AMPK), which senses the energy state of the cell and becomes activated under metabolic stress, inactivates by phosphorylation key enzymes in biosynthetic pathways thereby conserving ATP. In this paper, we studied the effect of AMPK activation and of protein phosphatase inhibitors, on the amino-acid-induced activation of p70S6K and ACC in hepatocytes in suspension. AMPK was activated under anoxic conditions or by incubation with 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAr) or oligomycin, an inhibitor of mitochondrial oxidative phosphorylation. Incubation of hepatocytes with amino acids activated p70S6K via multiple phosphorylation. It also activated ACC by a phosphatase-dependent mechanism but did not modify AMPK activation. Conversely, the amino-acid-induced activation of both ACC and p70S6K was blocked or reversed when AMPK was activated. This AMPK activation increased Ser79 phosphorylation in ACC but decreased Thr389 phosphorylation in p70S6K. Protein phosphatase inhibitors prevented p70S6K activation when added prior to the incubation with amino acids, whereas they enhanced p70S6K activation when added after the preincubation with amino acids. It is concluded that (a) AMPK blocks amino-acid-induced activation of ACC and p70S6K, directly by phosphorylating Ser79 in ACC, and indirectly by inhibiting p70S6K phosphorylation, and (b) both activation and inhibition of protein phosphatases are involved in the activation of p70S6K by amino acids. p70S6K adds to an increasing list of targets of AMPK in agreement with the inhibition of energy-consuming biosynthetic pathways. [source]

Mitochondrial copper metabolism and delivery to cytochrome c oxidase

IUBMB LIFE, Issue 7 2008
Darryl Horn
Abstract Metals are essential elements of all living organisms. Among them, copper is required for a multiplicity of functions including mitochondrial oxidative phosphorylation and protection against oxidative stress. Here we will focus on describing the pathways involved in the delivery of copper to cytochrome c oxidase (COX), a mitochondrial metalloenzyme acting as the terminal enzyme of the mitochondrial respiratory chain. The catalytic core of COX is formed by three mitochondrially-encoded subunits and contains three copper atoms. Two copper atoms bound to subunit 2 constitute the CuA site, the primary acceptor of electrons from ferrocytochrome c. The third copper, CuB, is associated with the high-spin heme a3 group of subunit 1. Recent studies, mostly performed in the yeast Saccharomyces cerevisiae, have provided new clues about 1) the source of the copper used for COX metallation; 2) the roles of Sco1p and Cox11p, the proteins involved in the direct delivery of copper to the CuA and CuB sites, respectively; 3) the action mechanism of Cox17p, a copper chaperone that provides copper to Sco1p and Cox11p; 4) the existence of at least four Cox17p homologues carrying a similar twin CX9C domain suggestive of metal binding, Cox19p, Cox23p, Pet191p and Cmc1p, that could be part of the same pathway; and 5) the presence of a disulfide relay system in the intermembrane space of mitochondria that mediates import of proteins with conserved cysteines motifs such as the CX9C characteristic of Cox17p and its homologues. The different pathways are reviewed and discussed in the context of both mitochondrial COX assembly and copper homeostasis. 2008 IUBMB IUBMB Life, 60(7): 421,429, 2008 [source]

Novel neuroprotective, neuritogenic and anti-amyloidogenic properties of 2,4-dinitrophenol: The gentle face of Janus

IUBMB LIFE, Issue 4 2006
Fernanda G. De Felice
Abstract In Roman mythology, Janus was the god of gates, doors, beginnings and endings. He was usually depicted with two faces looking in opposite directions. Janus was frequently used to symbolize change and transitions, such as the progression from past to future or from one viewpoint to another. 2,4-dinitrophenol (DNP) and other nitrophenols have long been known to be toxic at high concentrations (the 'bad' face of DNP), an effect that appears essentially related to interference with cellular energy metabolism due to uncoupling of mitochondrial oxidative phosphorylation. Five years ago, however, we published the first report showing that low concentrations of DNP protect neurons against the toxicity of the amyloid-, peptide (De Felice et al. (2001) FASEB J. 15:1297 - 1299]. Since then, other studies have provided evidence of beneficial actions of DNP (at low concentrations), including neuroprotection against different types of insult, blockade of amyloid aggregation, stimulation of neurite outgrowth and neuronal differentiation, and even extension of lifespan in certain organisms. Some of these effects appear to be due to mild mitochondrial uncoupling and prevention of cellular oxidative stress, whereas other actions are related to activation of additional intracellular signaling pathways. Thus, a novel and 'gentle' face of DNP is emerging from such studies. In this review, we discuss both toxic and beneficial actions of DNP. The evidence available so far suggests that DNP and other compounds with similar biological activities may be of significant interest to the development of novel therapeutic approaches for neurodegenerative diseases and other neurological disorders. iubmb Life, 58: 185-191, 2006 [source]

Mitochondrial dysfunction in a neural cell model of spinal muscular atrophy

Gyula Acsadi
Abstract Mutations of the survival motor neuron (SMN) gene in spinal muscular atrophy (SMA) lead to anterior horn cell death. The cause is unknown, but motor neurons depend substantially on mitochondrial oxidative phosphorylation (OxPhos) for normal function. Therefore, mitochondrial parameters were analyzed in an SMA cell culture model using small interfering RNA (siRNA) transfection that decreased Smn expression in NSC-34 cells to disease levels. Smn siRNA knock-down resulted in 35% and 66% reduced Smn protein levels 48 and 72 hr posttransfection, respectively. ATP levels were reduced by 14% and 26% at 48 and 72 hr posttransfection, respectively, suggesting decreased ATP production or increased energy demand in neural cells. Smn knock-down resulted in increased mitochondrial membrane potential and increased free radical production. Changes in activity of cytochrome c oxidase (CcO), a key OxPhos component, were observed at 72 hr with a 26% increase in oxygen consumption. This suggests a compensatory activation of the aerobic pathway, resulting in increased mitochondrial membrane potentials, a condition known to lead to the observed increase in free radical production. Further testing suggested that changes in ATP at 24 hr precede observable indices of cell injury at 48 hr. We propose that energy paucity and increased mitochondrial free radical production lead to accumulated cell damage and eventual cell death in Smn-depleted neural cells. Mitochondrial dysfunction may therefore be important in SMA pathology and may represent a new therapeutic target. 2009 Wiley-Liss, Inc. [source]

Fasting is neuroprotective following traumatic brain injury,

Laurie M. Davis
Abstract To determine the neuroprotective effect of fasting after traumatic brain injury (TBI) and to elucidate the potential underlying mechanisms, we used a controlled cortical impact (CCI) injury model to induce either a moderate or a severe injury to adult male Sprague Dawley rats. Tissue-sparing assessments were used to determine the level of neuroprotection of fasting, hypoglycemia (insulin 10 U), or ketone (1.66 mmoles/kg/day or 0.83 mmoles/kg/day; D-beta-hydroxtbutyrate) administration. Mitochondrial isolation and respiratory studies were utilized to determine the functionality of mitochondria at the site of injury. We also investigated biomarkers of oxidative stress, such as lipid/protein oxidation, reactive oxygen species (ROS) production, and intramitochondrial calcium load, as a secondary measure of mitochondrial homeostasis. We found that fasting animals for 24 hr, but not 48 hr, after a moderate (1.5 mm), but not severe (2.0 mm), CCI resulted in a significant increase in tissue sparing. This 24-hr fast also decreased biomarkers of oxidative stress and calcium loading and increased mitochondrial oxidative phosphorylation in mitochondria isolated from the site of injury. Insulin administration, designed to mimic the hypoglycemic effect seen during fasting did not result in significant tissue sparing after moderate CCI injury and in fact induced increased mortality at some injection time points. However, the administration of ketones resulted in increased tissue sparing after moderate injury. Fasting for 24 hr confers neuroprotection, maintains cognitive function, and improves mitochondrial function after moderate (1.5 mm) TBI. The underlying mechanism appears to involve ketosis rather than hypoglycemia. 2008 Wiley-Liss, Inc. [source]

Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the rat

Background: The pathogenesis of NSAID-induced gastrointestinal damage is believed to involve a nonprostaglandin dependent effect as well as prostaglandin dependent effects. One suggestion is that the nonprostaglandin mechanism involves uncoupling of mitochondrial oxidative phosphorylation. Aims: To assess the role of uncoupling of mitochondrial oxidative phosphorylation in the pathogenesis of small intestinal damage in the rat. Methods: We compared key pathophysiologic events in the small bowel following (i) dinitrophenol, an uncoupling agent (ii) parenteral aspirin, to inhibit cyclooxygenase without causing a ,topical' effect and (iii) the two together, using (iv) indomethacin as a positive control. Results: Dinitrophenol altered intestinal mitochondrial morphology, increased intestinal permeability and caused inflammation without affecting gastric permeability or intestinal prostanoid levels. Parenteral aspirin decreased mucosal prostanoids without affecting intestinal mitochondria in vivo, gastric or intestinal permeability. Aspirin caused no inflammation or ulcers. When dinitrophenol and aspirin were given together the changes in intestinal mitochondrial morphology, permeability, inflammation and prostanoid levels and the macro- and microscopic appearances of intestinal ulcers were similar to indomethacin. Conclusions: These studies allow dissociation of the contribution and consequences of uncoupling of mitochondrial oxidative phosphorylation and cyclooxygenase inhibition in the pathophysiology of NSAID enteropathy. While uncoupling of enterocyte mitochondrial oxidative phosphorylation leads to increased intestinal permeability and low grade inflammation, concurrent decreases in mucosal prostanoids appear to be important in the development of ulcers. [source]