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PubMed2006

Clinical treatments for mitochondrial dysfunctions after brain injury.

PURPOSE OF REVIEW: This review provides a comprehensive look at the evidence supporting the role of mitochondrial dysfunction in promoting neuronal death after acute brain injury, and critically discusses the most recent proposed therapies that could limit the deleterious effects of such a dysfunction on neurological outcome. RECENT FINDINGS: Following acute brain injury, disruption of calcium homeostasis, overproduction of reactive oxygen species, and opening of the mitochondrial permeability transition pore, are key factors in promoting mitochondrial dysfunction, with ensuing activation of either necrotic or apoptotic cell death pathways. Growing interest has been focused on developing new therapeutic strategies able to oppose these mechanisms. Several pharmacological agents are currently under investigation, including novel calcium channel blockers and antioxidants, uncoupling proteins and mitochondrial permeability transition pore inhibitors. Although a 'magic bullet' has not yet been identified, the results of both preclinical and clinical studies are encouraging. SUMMARY: Therapeutic interventions directly targeting processes and mechanisms responsible for mitochondrial dysfunction, may offer neuroprotection in brain-injured patients. The multifactorial cause of mitochondrial dysfunction suggests, however, the need for further studies aimed at clarifying optimal dose and time for drug administration, as well as the logical combination/sequence of those approaches that may ultimately achieve improvement in neurological outcome.

Blood Pressure↗
PubMed2006

Mitochondrial dysfunction and Alzheimer's disease.

Mitochondrial dysfunction has been implicated in causing metabolic abnormalities in Alzheimer's disease (AD). The searches for mitochondrial DNA variants associated with AD susceptibility have generated conflicting results. The age-related accumulation of somatic mitochondrial DNA deletion has been suggested to play a pathogenic role in the development of AD. Recent studies have demonstrated that amyloid-beta peptide (Abeta) progressively accumulates in mitochndrial matrix, as demonstrated in both transgenic mice over-expressing mutant amyloid precursor protein (APP) and autopsy brain from AD patients. Abeta-mediated mitochondrial stress was evidenced by impaired oxygen consumption and decreased respiratory chain complexes III and IV activities in brains from AD patients and AD-type transgenic mouse model. Furthermore, our studies indicated that interaction of intramitochondrial Abeta with a mitochondrial enzyme, amyloid binding alcohol dehydrogenase (ABAD), inhibits its enzyme activity, enhances generation of reactive oxygen species (ROS), impairs energy metabolism, and exaggerates Abeta-induced spatial learning/memory deficits and neuropathological changes in transgenic AD-type mouse model. Interception of ABAD-Abeta interaction may be a potential therapeutic strategy for Alzheimer's disease.

Alzheimer Disease↗
PubMed1999

Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues.

BACKGROUND: Zidovudine is commonly administered during pregnancy to prevent mother-to-child HIV-1 transmission. We investigated mitochondrial toxic effects in children exposed to zidovudine in utero and after birth. METHODS: We analysed observations of a trial of tolerance of combined zidovudine and lamivudine and preliminary results of a continuing retrospective analysis of clinical and biological symptoms of mitochondrial dysfunction in children born to HIV-1-infected women in France. Mitochondrial dysfunction was studied by spectrophotometry and polarography of respiratory-chain complexes in various tissues. FINDINGS: Eight children had mitochondrial dysfunction. Five, of whom two died, presented with delayed neurological symptoms and three were symptom-free but had severe biological or neurological abnormalities. Four of these children had been exposed to combined zidovudine and lamivudine, and four to zidovudine alone. No child was infected with HIV-1. All children had abnormally low absolute or relative activities of respiratory-chain complexes I, IV, or both months or years after the end of antiretroviral treatment. No mutation currently associated with constitutional disease was detected in any patient. INTERPRETATION: Our findings support the hypothesis of a link between mitochondrial dysfunction and the perinatal administration of prophylactic nucleoside analogues. Current recommendations for zidovudine monotherapy should however be maintained. Further assessment of the toxic effects of these drugs is required.

Acidosis, Lactic↗
PubMed1992

Topographic dissociation between mitochondrial dysfunction and cell death during low-flow hypoxia in perfused rat liver.

BACKGROUND: Although it has been postulated that mitochondrial dysfunction and oxygen radicals may play a role in the mechanisms of hypoxic liver injury, little is known about the intralobular topographic relationship between a disorder in oxygen metabolism and cell death during hypoxia. EXPERIMENTAL DESIGN: Intralobular heterogeneity of mitochondrial dysfunction and its topographic relationship to cell death during 25% low-flow hypoxia was visually demonstrated in perfused rat hepatic microcirculatory units by dual-color digital microfluorography using rhodamine 123, a fluorochrome sensitive to the mitochondrial membrane potential, and propidium iodide, which labels the nuclei of nonviable cells with a concomitant enhancement of fluorescence. RESULTS: In the normoperfused liver from fasted rats, no significant depletion of the mitochondrial membrane potential values was observed in any portion of lobules during 100 minutes. In the liver treated with the 40-minute hypoxia, the mitochondrial membrane potential values within the entire lobule were significantly decreased. After a longer period of hypoxia, the pericentral fluorescence decreased to background levels, and the intralobular gradient showed a steep decline midway between the periportal and pericentral regions. Cell death was at first prominent in the midzone at 40 minutes, and then extended towards the pericentral regions, forming centrilobular necrosis at 100 minutes. Although allopurinol diminished the early midzonal cell death and retarded the development of centrilobular necrosis, it did not attenuate depression of the mitochondrial membrane potential. CONCLUSIONS: It is conceivable that mitochondrial dysfunction per se may not be related to the intralobular distribution of cell death during hypoxia. On the other hand, mitochondrial dysfunction in the centrilobular regions seems to be an important event leading to early midzonal oxidative tissue damage in that this change may involve ATP breakdown and the subsequent enhancement of xanthine oxidase-mediated oxidative cell injury in the midzonal regions, which are incompletely oxygenated.

Animals↗
PubMed1988

The role of phospholipase in plasmocid-induced mitochondrial dysfunction in rat hearts.

This study was designed to clarify the role of phospholipase in the mechanism of plasmocid-induced mitochondrial dysfunction in the rat heart. Rats were divided into two groups: the control group, untreated; and the plasmocid group, in which plasmocid (30 mg/kg) was injected subcutaneously. In each group, the level of lipid peroxides and the phospholipase activity in heart homogenate were measured, and mitochondrial function (respiratory control index and the rate of oxygen consumption in State III) was determined polarographically. The activity of lysosomal enzymes (N-acetyl-beta-glucosaminidase and beta-glucuronidase) were also measured. The plasmocid group showed significant increases in lipid peroxide levels and phospholipase activity. Administration of plasmocid also caused mitochondrial dysfunction, while no significant changes were observed in the lysosomal enzyme activity of either group. These results suggested that plasmocid-induced mitochondrial dysfunction is based on the degrading of phospholipids by membrane bound phospholipase, and that lysosomal enzymes are unlikely to be involved in plasmocid-induced mitochondrial dysfunction.

Acetylglucosaminidase↗
PubMed1984

Improvement of the anoxia-induced mitochondrial dysfunction by membrane modulation.

The mitochondrial dysfunction induced by anoxia in vitro was improved with chlorpromazine, cepharanthine, bromophenacyl bromide, and mepacrine without affecting phospholipid or adenine nucleotide metabolisms. The drugs inhibited lipid peroxidation by Fe2+, mitochondrial disruption by Ca2+, and membrane perturbation by lysolecithin, and retained the activity to control H+ permeability across mitochondrial membranes. The drugs appeared to preserve the functions by acting to suppress the development of membrane deterioration which may have resided in the deenergization of mitochondria in the absence of oxygen.

Acetophenones↗
PubMed2005

Retrograde regulation due to mitochondrial dysfunction may be an important mechanism for carcinogenesis.

Mitochondrial dysfunction has crucial importance in carcinogenesis. Due to several reasons, it may lead to insufficiency in the electron transport chain, which activates a series of cytosolic proteins. These proteins are transported to the nucleus and promote the activation of genes leading to intracellular diverse metabolic, regulatory, signalization and stress-related pathways. Retrograde regulation is the general term for mitochondrial signaling, and is broadly defined as cellular responses to alterations in functional state of mitochondria. This signaling pathway is triggered by mitochondrial dysfunction. The retrograde response is not a simple On-Off switch, but rather it responds in a continuous manner to the changing metabolic needs of the cell. Communication between mitochondria and the nucleus is important for a variety of cellular processes such as carbohydrate and nitrogen metabolism, cell cycle and proliferation, and cell growth and morphogenesis. As a result of retrograde regulation, the cell, actually a component of the multicellular organism, transforms to a unicellular lifestyle and initiates a developing course, independent of the systemic structure. This transformed cell runs metabolic regulations effectively in order to utilize all energy depots, mainly the adipose tissue of the multicellular organism. The most important one is the active utilization of glyoxylate cycle, through which the malign cells supply glucose from fats. Continuously acting glycolysis and gluconeogenesis, fatty acid oxidation and de novo lipogenesis constitute futile cycles. This in turn causes cachexia by maintaining the organism in constant negative energy balance. Mitochondria-to-nucleus stress signaling activates some of the genes implicated in tumor progression and tumor cell metastasis. Retrograde regulation also renders the cell more resistant to apoptosis. It is becoming clearer which genes control the retrograde response in human cells. Most probably, MYC is one of the transcription factors necessary for this response.

Cell Transformation, Neoplastic↗
PubMed2005

Permanent threshold shift caused by acute cochlear mitochondrial dysfunction is primarily mediated by degeneration of the lateral wall of the cochlea.

Mitochondrial dysfunction in the cochlea is thought to be an important cause of sensorineural hearing loss. Recently, we have established a novel rat model with acute hearing impairment caused by exposure to the mitochondrial toxin 3-nitropropionic acid (3-NP) to analyze the mechanism of cochlear mitochondrial dysfunction. Both permanent and temporary threshold shifts were observed in this model depending on the amount of 3-NP used to induce hearing impairment. In this study, we demonstrate cochlear morphological changes in the permanent threshold shift model. Marked degeneration was detected in type 2 fibrocytes in the spiral prominence, type 4 fibrocytes in the spiral ligament, marginal cells and intermediate cells in the stria vascularis 3 h after 3-NP administration; these changes were progressive for at least 14 days. Less prominent degeneration was detected in type 1 and type 3 fibrocytes in the spiral ligament. These results indicate that permanent threshold shift caused by acute cochlear mitochondrial dysfunction is primarily mediated by cellular degeneration in the lateral wall of the cochlea, and suggest that therapy of cochlear hearing loss due to acute energy failure may be achieved through protection and regeneration of the cochlear lateral wall.

Acute Disease↗
PubMed1998

Catecholamines potentiate amyloid beta-peptide neurotoxicity: involvement of oxidative stress, mitochondrial dysfunction, and perturbed calcium homeostasis.

Oxidative stress and mitochondrial dysfunction are implicated in the neuronal cell death that occurs in physiological settings and in neurodegenerative disorders. In Alzheimer's disease (AD) degenerating neurons are associated with deposits of amyloid beta-peptide (A beta), and there is evidence for increased membrane lipid peroxidation and protein oxidation in the degenerating neurons. Cell culture studies have shown that A beta can disrupt calcium homeostasis and induce apoptosis in neurons by a mechanism involving oxidative stress. We now report that catecholamines (norepinephrine, epinephrine, and dopamine) increase the vulnerability of cultured hippocampal neurons to A beta toxicity. The catecholamines were effective in potentiating A beta toxicity at concentrations of 10-200 microM, with the higher concentrations (100-200 microM) themselves inducing cell death. Serotonin and acetylcholine were not neurotoxic and did not modify A beta toxicity. Levels of membrane lipid peroxidation, and cytoplasmic and mitochondrial reactive oxygen species, were increased following exposure to neurons to A beta, and catecholamines exacerbated the oxidative stress. Subtoxic concentrations of catecholamines exacerbated decreases in mitochondrial energy charge and transmembrane potential caused by A beta, and higher concentrations of catecholamines alone induced mitochondrial dysfunction. Antioxidants (vitamin E, glutathione, and propyl gallate) protected neurons against the damaging effects of A beta and catecholamines, whereas the beta-adrenergic receptor antagonist propanolol and the dopamine (D1) receptor antagonist SCH23390 were ineffective. Measurements of intracellular free Ca2+ ([Ca2+]i) showed that A beta induced a slow elevation of [Ca2+]i which was greatly enhanced in cultures cotreated with catecholamines. Collectively, these data indicate a role for catecholamines in exacerbating A beta-mediated neuronal degeneration in AD and, when taken together with previous findings, suggest roles for oxidative stress induced by catecholamines in several different neurodegenerative conditions.

Amyloid beta-Peptides↗
PubMed2003

Persistent mitochondrial dysfunction in HIV-1-exposed but uninfected infants: clinical screening in a large prospective cohort.

BACKGROUND: Antiretroviral prevention of mother to child HIV-1 is established but tolerance remains to be assessed. AIM To determine the risk for persistent mitochondrial dysfunction in HIV-uninfected children born to seropositive mothers. METHOD: An exhaustive study in a large prospective cohort with predetermined algorithm of the unexplained symptoms compatible with mitochondrial dysfunction. A total of 2644 of 4392 children were exposed to antiretrovirals. Complementary investigations were carried out on a case-by-case basis using classification with a diagnostic probability scale, based on experience with constitutional diseases. A spontaneous notification register for children not included in the cohort was created. RESULTS: Good circumstantial evidence of mitochondrial dysfunction was found for twelve children. Seven were from the cohort. All presented neurological symptoms, often associated with abnormal magnetic resonance image (10 of 12) and/or a significant episode of hyperlactatemia (seven of 12). All had either a profound deficit in one of the respiratory chain complexes (11 of 12) and/or a typical histological pattern (two of 12). All were perinatally exposed to antiretrovirals. None of them had perinatal morbidity that could explain this symptomatology. The 18-month incidence was 0.26% (95% confidence interval, 0.10-0.54) in exposed children, in comparison with the general figure of 0.01% for paediatric neuro-mitochondrial diseases in the general population. Fourteen other children in the cohort, all exposed to antiretrovirals, had unexplained symptoms, mostly neurological, for which one of the possible differential diagnoses was mitochondrial dysfunction. Close similarities in clinical, neuroradiological and histological findings strongly suggest a common pathological process in all these 26 children. CONCLUSION: Children exposed to nucleoside analogues during the perinatal period are at risk of a neurological syndrome associated with persistent mitochondrial dysfunction.

Anti-HIV Agents↗
PubMed2003

Alterations of rCBF and mitochondrial dysfunction in major depressive disorder: a case report.

OBJECTIVE: A mitochondrial disease might be considered when depressive disorder is associated with diabetes mellitus or other symptoms commonly found in mitochondrial disease. Scattered regional cerebral blood flow (rCBF) decreases and increases have been reported in depressive and mitochondrial disorders. A 61-year-old male patient with early adult onset of depressive disorder and a slowly developing multiorgan syndrome including diabetes mellitus was investigated. METHOD: 99mTc-HMPAO rCBF SPECT and muscle biopsy to assess mitochondrial functions were performed in the patient. RESULTS: Alterations of rCBF were found in the patient, with the most pronounced decreases in the left dorsolateral frontal and inferior parietal lobes, and the most pronounced increases in the bilateral superior parietal lobes. Muscle biopsy revealed myopathy and decrease of mitochondrial adenosine triphosphate production rates (MAPRs). CONCLUSION: The MAPRs decreases support the suspicion of mitochondrial dysfunction in the patient. A subgroup of depressed patients may have mitochondrial dysfunctions.

Brain↗
PubMed2005

Mitochondrial dysfunction as an initiating event in atherogenesis: a plausible hypothesis.

It is now widely accepted that oxidant stress and the ensuing endothelial dysfunction play a key role in the pathogenesis of atherosclerosis and cardiovascular diseases. The mitochondrial respiratory chain is the major source of reactive oxygen species as byproducts of normal cell respiration. Mitochondria may also be important targets for reactive oxygen species, which may damage mitochondrial lipids, enzymes and DNA with following mitochondrial dysfunction. Free cholesterol, oxidized low-density lipoprotein and glycated high-density lipoprotein are further possible causes of mitochondrial dysfunction and/or apoptosis. Moreover, in patients with mitochondrial diseases, vascular complications are commonly observed at an early age, often in the absence of traditional risk factors for atherosclerosis. We propose that mitochondrial dysfunction, besides endothelial dysfunction, represents an important early step in the chain of events leading to atherosclerotic disease.

Animals↗
PubMed2003

UCP-mediated energy depletion in skeletal muscle increases glucose transport despite lipid accumulation and mitochondrial dysfunction.

To address the potential role of lipotoxicity and mitochondrial function in insulin resistance, we studied mice with high-level expression of uncoupling protein-1 in skeletal muscle (UCP-H mice). Body weight, body length, and bone mineral density were decreased in UCP-H mice compared with wild-type littermates. Forelimb grip strength and muscle mass were strikingly decreased, whereas muscle triglyceride content was increased fivefold in UCP-H mice. Electron microscopy demonstrated lipid accumulation and large mitochondria with abnormal architecture in UCP-H skeletal muscle. ATP content and key mitochondrial proteins were decreased in UCP-H muscle. Despite mitochondrial dysfunction and increased intramyocellular fat, fasting serum glucose was 22% lower and insulin-stimulated glucose transport 80% higher in UCP-H animals. These beneficial effects on glucose metabolism were associated with increased AMP kinase and hexokinase activities, as well as elevated levels of GLUT4 and myocyte enhancer factor-2 proteins A and D in skeletal muscle. These results suggest that UCP-H mice have a mitochondrial myopathy due to depleted energy stores sufficient to compromise growth and impair muscle function. Enhanced skeletal muscle glucose transport in this setting suggests that excess intramyocellular lipid and mitochondrial dysfunction are not sufficient to cause insulin resistance in mice.

Animals↗
PubMed2000

Lack of evidence of mitochondrial dysfunction in the offspring of HIV-infected women. Retrospective review of perinatal exposure to antiretroviral drugs in the Perinatal AIDS Collaborative Transmission Study.

A recent report suggesting mitochondrial dysfunction among eight HIV-exposed but uninfected children exposed perinatally to nucleoside reverse transcriptase inhibitors (NRTIs) prompted a review within the Perinatal AIDS Collaborative Transmission Study (PACTS). A standardized retrospective review was conducted of 118 deaths at < 5 years. Deaths were classified as unrelated to mitochondrial dysfunction (Class 1), unlikely related (Class 2), possibly related (Class 3), or likely related or proven (Class 4). Among 35 deaths recorded in HIV-uninfected or indeterminate children, none were classified in either Class 2, 3, or 4. We also reviewed signs or symptoms consistent with possible mitochondrial dysfunction among 1,954 living uninfected children. Only one child was in Class 3 and two siblings were in Class 2; none had perinatal antiretroviral drug exposure. We found no evidence indicating that uninfected infants exposed to perinatal NRTIs died of mitochondrial disorders or that living exposed children had symptoms of mitochondrial dysfunction.

Acquired Immunodeficiency Syndrome↗
PubMed2006

The not so 'mighty chondrion': emergence of renal diseases due to mitochondrial dysfunction.

Mitochondria are intracellular organelles with a variety of vital functions, including the provision of energy in the form of adenosine 5'-triphosphate. Increasingly, we are becoming more aware of the importance of mitochondrial dysfunction in a number of common medical conditions. In this review and overview, we focus on the growing evidence that mitochondrial dysfunction is involved in either the etiology or underlying pathophysiology of a broad spectrum of renal diseases, including acute renal injury due to ischemia-reperfusion injury, renal Fanconi syndrome, and glomerular disorders such as focal segmental glomerulosclerosis. In addition, mitochondrial dysfunction may also contribute to the growing burden of chronic kidney disease seen in our aging population, which is still largely unexplained. Unfortunately, at present, our ability to diagnose and treat renal disorders related to mitochondrial dysfunction is limited, and further work in this field is needed.

Animals↗
PubMed2007

Mitochondrial dysfunction as the molecular basis of bipolar disorder: therapeutic implications.

Multiple lines of evidence, such as impaired energy metabolism in the brain detected by magnetic resonance spectroscopy, a possible role of maternal inheritance, co-morbidity with mitochondrial diseases, the effects of mood stabilisers on mitochondria, increased mitochondrial DNA (mtDNA) deletion in the brain, and association with mtDNA mutations/polymorphisms or nuclear-encoded mitochondrial genes, suggest that mitochondrial dysfunction is an important component of bipolar disorder. Global reduction of mitochondria-related gene expression in the postmortem brains of patients with bipolar disorder may also be an indicator, but such findings are affected by sample pH and thus need to be interpreted with caution. A recently developed animal model carrying mtDNA deletion in neurons suggested that accumulation of mtDNA deletions causes bipolar disorder-like phenotypes. The next step in the study of mitochondrial dysfunction in bipolar disorder should be clarification of how mitochondrial dysfunction, a nonspecific risk factor, can cause specific symptoms of bipolar disorder. Two hypothetical mechanisms are mtDNA neuroplasticity and nonvisual photoreception impairment. Further study of mitochondrial dysfunction in bipolar disorder is expected to be useful for the development of new mood stabilisers.

Animals↗
PubMed2003

Mitochondrial dysfunction and reactive oxygen species in excitotoxicity and apoptosis: implications for the pathogenesis of neurodegenerative diseases.

In recent years we have witnessed a major interest in the study of the role of mitochondria, not only as ATP producers through oxidative phosphorylation but also as regulators of intracellular Ca2+ homeostasis and endogenous producers of reactive oxygen species (ROS). Interestingly, the mitochondria have been also implicated as central executioners of cell death. Increased mitochondrial Ca2+ overload as a result of excitotoxicity has been associated with the generation of superoxide and may induce the release of proapoptotic mitochondrial proteins, proceeding through DNA fragmentation/condensation and culminating in cell demise by apoptosis and/or necrosis. In addition, these processes have been implicated in the pathogenesis of many neurodegenerative diseases, which share several features of cell death: selective brain areas undergo neurodegeneration, involving mitochondrial dysfunction (mitochondrial complexes are affected), loss of intracellular Ca2+ homeostasis, excitotoxicity, and the extracellular or intracellular accumulation of insoluble protein aggregates in the brain.

Alzheimer Disease↗
PubMed1984

The role of phospholipase in mitochondrial dysfunction after coronary reperfusion in the canine myocardium.

The left anterior descending coronary artery of a dog was occluded for 15 min followed by a 5 min reperfusion in order to investigate the mechanism responsible for the paradoxical exacerbation of heart mitochondrial dysfunction caused by reperfusion. The mitochondrial function was assessed and the concentration of Ca++, phospholipids and free fatty acids (FFA) were determined. The relative importance of mitochondrial lysophospholipids was also investigated. Eleven dogs (30.6%) developed "reperfusion arrhythmia" (arrhythmia group) but 25 did not (control group). Although mitochondrial dysfunction was observed in the reperfused area even in the control group, a greater impairment of mitochondrial function was observed in the reperfused area in the arrhythmia group. There was no significant difference in the contents of FFA and phospholipids in the mitochondria from the normal area of both groups and from the reperfused area of the control group. However, a marked increase in eight FFA and a significant decrease in phospholipids were observed in the mitochondria from the reperfused area of the arrhythmia group. A significant increase in Ca++ content both in the myocardium and the mitochondria from the reperfused area was observed in the arrhythmia group but not in the control group. In separate experiments, the mitochondria prepared from dog left ventricle were incubated with either phospholipase C (PhC) or phospholipase A2 ( PhA2 ). Both phospholipases induced severe mitochondrial dysfunction. PhC induced a significant increase in FFA, quite analogous to the changes in mitochondrial FFA caused by reperfusion in vivo. PhA2 also induced a tremendous increase in FFA but only in the content of unsaturated FFA. Although PhC did not affect the lysophospholipid profiles, PhA2 induced lysophosphatidyl choline. These results indicate that mitochondrial damages characteristic of the early phase of coronary reperfusion may be caused by the action of PhC, activated by increased intracellular Ca++, which in turn induces degradation of the mitochondrial membrane.

Acyl Coenzyme A↗