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At least 19 recordsLinked to original sources
PubMed1995

Calcium ion-dependent signalling and mitochondrial dysfunction: mitochondrial calcium uptake during hormonal stimulation in intact liver cells and its implication for the mitochondrial permeability transition.

Hormones that elevate cytosolic Ca2+ concentrations ([Ca2+]cyt) often use Ca2+ as a messenger to activate intramitochondrial metabolic processes. However, the mitochondrial Ca2+ level also regulates the activation of the mitochondrial permeability transition (MPT), a process that involves the assembly of a high conductance proteinaceous pore across the inner and outer membrane. Studies on intact liver cells indicate that the MPT is a critical step in the cell killing induced by anoxia or respiratory inhibitors. In this study, we used freshly isolated hepatocytes to investigate to what extent the elevation of [Ca2+]cyt by vasopressin or other agonists causes Ca2+ accumulation in the mitochondria and how this treatment affects the mitochondrial susceptibility to undergo the MPT. Hepatocytes were incubated with vasopressin, glucagon, or with thapsigargin (an inhibitor of the endoplasmic reticulum Ca2+ pump) prior to permeabilization with digitonin. Mitochondrial Ca2+ accumulation was determined by following the ionomycin-induced Ca2+ release in permeabilized cells and mitochondrial swelling was studied by following cyclosporin A-sensitive light scattering changes induced by phenyl-arsenoxide and rotenone. The results indicate that agents that elevate [Ca2+]cyt cause a significant Ca2+ accumulation in the mitochondria. Excessive Ca2+ accumulation (> 10-fold increase over basal levels) was obtained with the combination of vasopressin and glucagon or with incubations containing thapsigargin. These conditions were also associated with a marked increase in rotenone-induced mitochondrial swelling. However, the more modest increase in mitochondrial Ca2+ content after treating cells with vasopressin alone did not enhance the swelling response; instead, vasopressin suppressed mitochondrial swelling compared to control incubations. Vasopressin also partly suppressed the swelling associated with thapsigargin treatment, although it did not significantly affect the Ca2+ accumulation under these conditions. This effect of vasopressin was mimicked by phorbol ester, suggesting a role for protein kinase C. The data indicate that mitochondrial Ca2+ accumulation following elevation of elevation of [Ca2+]cyt enhances the susceptibility for activation of the MPT, a response that may increase cell injury during anoxia or in response to other challenges. However, hormones also activate protective responses in the cell that suppress the MPT.

Animals↗
PubMed2006

Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction.

Mitochondrial dysfunction is one of the major intracellular lesions of Alzheimer's disease (AD). However, the causative factors involved in the mitochondrial dysfunction in human AD are not well understood. Here we report that nonglycosylated full-length and C-terminal truncated amyloid precursor protein (APP) accumulates exclusively in the protein import channels of mitochondria of human AD brains but not in age-matched controls. Furthermore, in AD brains, mitochondrially associated APP formed stable approximately 480 kDa complexes with the translocase of the outer mitochondrial membrane 40 (TOM40) import channel and a super complex of approximately 620 kDa with both mitochondrial TOM40 and the translocase of the inner mitochondrial membrane 23 (TIM23) import channel TIM23 in an "N(in mitochondria)-C(out cytoplasm)" orientation. Accumulation of APP across mitochondrial import channels, which varied with the severity of AD, inhibited the entry of nuclear-encoded cytochrome c oxidase subunits IV and Vb proteins, which was associated with decreased cytochrome c oxidase activity and increased levels of H2O2. Regional distribution of mitochondrial APP showed higher levels in AD-vulnerable brain regions, such as the frontal cortex, hippocampus, and amygdala. Mitochondrial accumulation of APP was also observed in the cholinergic, dopaminergic, GABAergic, and glutamatergic neuronal types in the category III AD brains. The levels of translocationally arrested mitochondrial APP directly correlated with mitochondrial dysfunction. Moreover, apolipoprotein genotype analysis revealed that AD subjects with the E3/E4 alleles had the highest content of mitochondrial APP. Collectively, these results suggest that abnormal accumulation of APP across mitochondrial import channels, causing mitochondrial dysfunction, is a hallmark of human AD pathology.

Alzheimer Disease↗
PubMed2001

Development of lipophilic cations as therapies for disorders due to mitochondrial dysfunction.

Mitochondrial dysfunction causes or exacerbates a number of diseases. These include genetic disorders such as Friedreich's ataxia where the primary lesion is a defect in a nuclear gene and those diseases caused by mutations to mitochondrial DNA. Mitochondrial damage also contributes to neurodegenerative diseases, diabetes and ischaemia-reperfusion injury. Drug therapies to prevent or alleviate mitochondrial dysfunction use redox active compounds, anti-oxidants or mitochondrial co-factors, however, their effectiveness is limited. A promising approach to increase the selectivity and potency of these compounds is to modify them so that they concentrate within mitochondria. This can be done by incorporating a lipophilic cation which causes the molecules to concentrate several hundred-fold in mitochondria, driven by the membrane potential across the inner membrane. As lipophilic cations cross biological membranes easily, they can be delivered to mitochondria of the heart, brain and skeletal muscle, the organs most affected by mitochondrial damage. Mitochondria-targeted lipophilic cations may lead to improved therapies for diseases involving mitochondrial dysfunction.

Animals↗
PubMed2001

Genome-wide responses to mitochondrial dysfunction.

Mitochondrial dysfunction can lead to diverse cellular and organismal responses. We used DNA microarrays to characterize the transcriptional responses to different mitochondrial perturbations in Saccharomyces cerevisiae. We examined respiratory-deficient petite cells and respiratory-competent wild-type cells treated with the inhibitors of oxidative phosphorylation antimycin, carbonyl cyanide m-chlorophenylhydrazone, or oligomycin. We show that respiratory deficiency, but not inhibition of mitochondrial ATP synthesis per se, induces a suite of genes associated with both peroxisomal activities and metabolite-restoration (anaplerotic) pathways that would mitigate the loss of a complete tricarboxylic acid cycle. The array data suggested, and direct microscopic observation of cells expressing a derivative of green fluorescent protein with a peroxisomal matrix-targeting signal confirmed, that respiratory deficiency dramatically induces peroxisome biogenesis. Transcript profiling of cells harboring null alleles of RTG1, RTG2, or RTG3, genes known to control signaling from mitochondria to the nucleus, suggests that there are multiple pathways of cross-talk between these organelles in yeast.

Antimycin A↗
PubMed2006

Phospholipases A2 mediate amyloid-beta peptide-induced mitochondrial dysfunction.

Mitochondrial dysfunction has been implicated in the pathophysiology of Alzheimer's disease (AD) brains. To unravel the mechanism(s) underlying this dysfunction, we demonstrate that phospholipases A2 (PLA2s), namely the cytosolic and the calcium-independent PLA2s (cPLA2 and iPLA2), are key enzymes mediating oligomeric amyloid-beta peptide (Abeta(1-42))-induced loss of mitochondrial membrane potential and increase in production of reactive oxygen species from mitochondria in astrocytes. Whereas the action of iPLA2 is immediate, the action of cPLA2 requires a lag time of approximately 12-15 min, probably the time needed for initiating signaling pathways for the phosphorylation and translocation of cPLA2 to mitochondria. Western blot analysis indicated the ability of oligomeric Abeta(1-42) to increase phosphorylation of cPLA2 in astrocytes through the NADPH oxidase and mitogen-activated protein kinase pathways. The involvement of PLA2 in Abeta(1-42)-mediated perturbations of mitochondrial function provides new insights to the decline in mitochondrial function, leading to impairment in ATP production and increase in oxidative stress in AD brains.

Amyloid beta-Peptides↗
PubMed2004

Surgical and anesthetic management of patients with mitochondrial dysfunction.

Mitochondrial diseases are primary defects in bio-energy metabolism. They are a heterogeneous group of diseases. The specific constellation of symptoms that will manifest in the effected individual depends on the type of genetic defect in the mitochondria. The goals of medical management, expressed in a highly simplified fashion, are to maintain a normal acid-base balance and to avoid those medical conditions and situations that add extra stress to a compromised bio-energy production system. Infection is a common stress that may cause a crisis in a patient with mitochondrial dysfunction. Treatment and avoidance of infections is a goal of both medical and surgical management. Common childhood illness such as otitis media, tonsillitis and sinusitis are example of such stress inducing infections.

Journal Article↗
PubMed2003

Liver failure caused by herpes simplex virus thymidine kinase plus ganciclovir therapy is associated with mitochondrial dysfunction and mitochondrial DNA depletion.

Herpes simplex virus thymidine kinase (HSV-tk) converts ganciclovir (GCV) into an active compound, which can be incorporated into DNA molecules and terminate DNA synthesis. Gene transfer of HSV-tk followed by GCV administration has been used with success to treat experimental cancer and this strategy has entered into clinical trials. Although it is thought that the cytotoxic effect occurs mainly in tumoral dividing cells, where mitotic activity favors integration of the genotoxic compound into nuclear DNA, there are concerns of potential damage to normal nondividing cells. In the present work we have explored the mechanisms of HSV-tk/GCV toxicity and in particular whether this therapy may cause lesions of mitochondrial DNA (mtDNA) and mitochondrial dysfunction. We found that the administration of GCV to rats injected with adenovirus encoding HSV-tk induced hepatocellular damage characterized by the presence of apoptotic bodies, ballooning of hepatocytes, and severe hepatic steatosis with mitochondria enlargement and cristae dissolution at the ultrastructural level. Remarkably, Southern blot analysis showed substantial reduction in the amount of mtDNA in the liver. Using radiolabeled GCV we could demonstrate incorporation of this compound into both nuclear and mtDNA in HSV-tk-transduced rat hepatocytic cell line MCA-RH7777 and subsequent alteration of mitochondrial function. Our observations confirm that GCV can damage both nuclear and mtDNA in cells transduced with HSV-tk and that this effect could be responsible for severe mitochondrial dysfunction and toxicity in normal nondividing cells. These data are relevant for the design of clinical trials using adenoviral vectors encoding HSV-tk.

Adenoviridae↗
PubMed1995

Mitochondrial bioactivation of cysteine S-conjugates and 4-thiaalkanoates: implications for mitochondrial dysfunction and mitochondrial diseases.

The toxicity of most drugs and chemicals is associated with their enzymatic conversion to toxic metabolites. Bioactivation reactions occur in a range of organs and organelles, including mitochondria. The toxicity of haloalkene-derived cysteine S-conjugates and related 4-thiaalkanoates is associated with their mitochondrial bioactivation. Toxic cysteine S-conjugates are formed by the glutathione S-transferase-catalyzed addition of glutathione to haloalkenes to give glutathione S-conjugates, which are hydrolyzed by gamma-glutamyltransferase and dipeptidases. Mitochondrial cysteine conjugate beta-lyase-catalyzed bioactivation of cysteine S-conjugates affords unstable alpha-halothiolates. Haloalkene-derived 4-thiaalkanoates, which are analogs of cysteine S-conjugates that lack an alpha-amino group, undergo bioactivation by the enzymes of fatty acid beta-oxidation to give 3-hydroxy-4-thiaalkanoates that eliminate alpha-halothiolates. alpha-Halothiolates yield alkylating and acylating agents that interact with cellular macromolecules and thereby cause cell damage. Mitochondrial dysfunction is the hallmark of cysteine S-conjugate-induced cytotoxicity: decreased respiration, decreased ATP and total adenine nucleotide concentrations, depletion of the mitochondrial glutathione content, perturbations in cellular Ca2+ homeostasis, and damage to the mitochondrial genome are seen with cysteine S-conjugates. Similar changes are observed with cytotoxic 4-thiaalkanoates, but inhibition of the medium-chain acyl-CoA dehydrogenase and hypoglycemia are also observed.

Animals↗
PubMed2000

Organismal effects of mitochondrial dysfunction.

Mitochondrial disease can lead to clinical abnormalities in any organ system. Both inherited and spontaneous disorders are known. The spontaneous forms can occur as a mitochondrial DNA (mtDNA) mutation early in embryogenesis or, later in life, as somatic mutations that accumulate with age. The inherited forms may arise from any of >100 characterized mutations in mtDNA or from >200 nuclear gene defects that affect proteins required for mitochondrial function. Most dividing cells survive and interact normally despite their mitochondrial defects. Thus post-mitotic, terminally differentiated cells are preferentially affected in mitochondrial disease. This review emphasizes cellular metabolic co-operation and the structural and biochemical diversity of mitochondria as the framework for understanding the clinical spectrum of mitochondrial disease. The principles of the mitochondrial clinical assessment scale I (MCAS-I) are presented to assist in the development of diagnostic spectra of mitochondrial disease.

Animals↗
PubMed2006

Role of mitochondrial dysfunction and mitochondrial DNA mutations in age-related hearing loss.

Mitochondrial DNA (mtDNA) mutations/deletions are considered to be associated with the development of age-related hearing loss (AHL). We assessed the role of accumulation of mtDNA mutations in the development of AHL using Polg(D257A) knock-in mouse, which exhibited increased spontaneous mtDNA mutation rates during aging and showed accelerated aging primarily due to increased apoptosis. They exhibited moderate hearing loss and degeneration of the hair cells, spiral ganglion cells and stria vascularis by 9 month of age, while wild-type animals did not. We next examined if mitochondrial damage induced by systemic application of germanium dioxide caused progressive hearing loss and cochlear damage. Guinea pigs and mice given germanium dioxide exhibited degeneration of the muscles and kidney and developed hearing loss due to degeneration of cochlear tissues, including the stria vascularis. Calorie restriction, which causes a metabolic shift toward increased energy metabolism in some organs, has been shown to attenuate AHL and age-related cochlear degeneration and to lower quantity of mtDNA deletions in the cochlea of mammals. Together these findings indicate that decreased energy metabolism due to accumulation of mtDNA mutations/deletions and decline of respiratory chain function play an important role in the manifestation of AHL.

Animals↗
PubMed2004

A novel animal model of acute cochlear mitochondrial dysfunction.

Acute mitochondrial dysfunction in the cochlea is likely to result in hearing loss as a consequence of local energy shortage, similar to ischemia- or noise-induced hearing loss. To establish an animal model of acute cochlear mitochondrial dysfunction, we applied a mitochondrial toxin, 3-nitropropionic acid (3-NP) in the rat cochlea. Rats treated with 500mM 3-NP exhibited permanent threshold shifts in acoustic brainstem response while the same volume of 300mM 3-NP caused temporary threshold shifts. Histological examination in the permanent threshold shift model revealed severe degeneration of fibrocytes within spiral ligament and spiral limbus, indicating these cells are vulnerable to acute mitochondrial dysfunction. This model represents a novel tool for investigating the pathophysiology of acute cochlear mitochondrial dysfunction.

Animals↗
PubMed2001

Dysfunctional mitochondrial respiration in the wobbler mouse brain.

The involvement of mitochondrial dysfunction promoting neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), has been suggested. Histopathological and biochemical mitochondrial abnormalities have been reported in both sporadic and familial patients and suggest the contention that mitochondria may play a key role promoting ALS. Animal models of ALS provide a unique opportunity to study this incurable and fatal human disease. In the present study we tested the hypothesis that alterations in mitochondrial physiology occur in the brain of wobbler mice. No significant difference was found in the respiratory control index or adenosine diphosphate/oxygen ratio values between isolated mitochondria of wobbler and control mice. When pyruvate and malate were used as substrates, oxygen consumption was decreased significantly by approximately 33% in mitochondria isolated from wobbler mouse brain compared to controls. Oxygen consumption in the presence of ascorbate and N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) was decreased significantly by approximately 21% in wobbler brain mitochondria compared to controls, which suggests impairment in the function of complex IV. These findings are the first demonstration of mitochondrial respiratory chain dysfunction in the brain of the wobbler mouse.

Amyotrophic Lateral Sclerosis↗
PubMed2002

Top down analysis ceramide-induced mitochondrial dysfunctions: role of mitochondrial swelling.

Mitochondrial role in ceramide-induced apoptosis pathway remains unclear. Direct effects of ceramide on mitochondria (cytochrome c release, respiratory chain inhibition, oxygen radicals production...) have been reported [1, 2] and we previously showed that addition of ceramide to intact cells or isolated mitochondria triggers mitochondrial swelling which appeared to be insensitive to cyclosporin A (CsA) [3, 4]. The purpose of this work was to determine to which extent this CsA-insensitive mitochondrial swelling, therefore distinct from permeability transition, participates to ceramide-induced apoptosis. To achieve this, we applied Top-Down analysis of integrated mitochondrial function [5], in order to better understand ceramide-induced mitochondrial dysfunctions.

Animals↗
PubMed1991

Introduction of disease-related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction.

Mutant mitochondrial DNA with large-scale deletions (delta-mtDNA) has been frequently observed in patients with chronic progressive external ophthalmoplegia (CPEO), a subgroup of the mitochondrial encephalomyopathies. To exclude involvement of the nuclear genome in expression of the mitochondrial dysfunction characteristic of CPEO, we introduced the mtDNA of a CPEO patient into clonal mtDNA-less HeLa cells and isolated cybrid clones. Quantitation of delta-mtDNA in the cybrids revealed that delta-mtDNA was selectively propagated with higher levels of delta-mtDNA correlating with slower cellular growth rate. In these cybrid clones, translational complementation of the missing tRNAs occurred only when delta-mtDNA was less than 60% of the total mtDNA, whereas accumulation of delta-mtDNA to greater than 60% resulted in progressive inhibition of overall mitochondrial translation as well as reduction of cytochrome c oxidase activity throughout the organelle population. Because these cybrids shared the same nuclear background as HeLa cells, these results suggest that large-scale deletion mutations of mtDNA alone are sufficient for the mitochondrial dysfunction characteristic of CPEO.

Adolescent↗
PubMed2006

Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology.

Many muscular and neurological disorders are associated with mitochondrial dysfunction and are often accompanied by changes in mitochondrial morphology. Mutations in the gene encoding OPA1, a protein required for fusion of mitochondria, are associated with hereditary autosomal dominant optic atrophy type I. Here we show that mitochondrial fragmentation correlates with processing of large isoforms of OPA1 in cybrid cells from a patient with myoclonus epilepsy and ragged-red fibers syndrome and in mouse embryonic fibroblasts harboring an error-prone mitochondrial mtDNA polymerase gamma. Furthermore, processed OPA1 was observed in heart tissue derived from heart-specific TFAM knock-out mice suffering from mitochondrial cardiomyopathy and in skeletal muscles from patients suffering from mitochondrial myopathies such as myopathy encephalopathy lactic acidosis and stroke-like episodes. Dissipation of the mitochondrial membrane potential leads to fast induction of proteolytic processing of OPA1 and concomitant fragmentation of mitochondria. Recovery of mitochondrial fusion depended on protein synthesis and was accompanied by resynthesis of large isoforms of OPA1. Fragmentation of mitochondria was prevented by overexpressing OPA1. Taken together, our data indicate that proteolytic processing of OPA1 has a key role in inducing fragmentation of energetically compromised mitochondria. We present the hypothesis that this pathway regulates mitochondrial morphology and serves as an early response to prevent fusion of dysfunctional mitochondria with the functional mitochondrial network.

Animals↗
PubMed1994

Nuclear but not mitochondrial genome involvement in human age-related mitochondrial dysfunction. Functional integrity of mitochondrial DNA from aged subjects.

The role of mtDNA and nuclear genome in human aging was examined by their intercellular transfer using skin fibroblasts and mtDNA-less HeLa cells (rho o-HeLa cells). We found in vivo age-related reductions in the activity of cytochrome c oxidase in human skin fibroblasts obtained from 16 donors of various ages (0-97 years). The abnormality in mitochondria of the aged donors was not attributable to either decrease in the copy number of mtDNA molecules or increase in the copy number of deletion mutant mtDNA molecules, but to significant decrease in overall polypeptide synthesis in the mitochondria. However, intercellular mtDNA transfer experiments showed that fibroblast mtDNA from elderly donors is functionally intact. By contrast, intercellular transfer of HeLa nuclei to fibroblasts from aged donors restored cytochrome c oxidase activity, suggesting that the age-related phenotype was nuclear recessive. However, during subsequent cultivation of these hybrids, the activity gradually reduced again, associated with gradual chromosome loss. These observations support the idea that accumulation of nuclear recessive somatic mutations, but not mtDNA mutations, is responsible for the in vivo age-related mitochondrial dysfunction observed in human skin fibroblasts.

Aged↗
PubMed2002

Mitochondrial dysfunction due to oxidative mitochondrial DNA damage is reduced through cooperative actions of diverse proteins.

The mitochondrial genome is a significant target of exogenous and endogenous genotoxic agents; however, the determinants that govern this susceptibility and the pathways available to resist mitochondrial DNA (mtDNA) damage are not well characterized. Here we report that oxidative mtDNA damage is elevated in strains lacking Ntg1p, providing the first direct functional evidence that this mitochondrion-localized, base excision repair enzyme functions to protect mtDNA. However, ntg1 null strains did not exhibit a mitochondrial respiration-deficient (petite) phenotype, suggesting that mtDNA damage is negotiated by the cooperative actions of multiple damage resistance pathways. Null mutations in ABF2 or PIF1, two genes implicated in mtDNA maintenance and recombination, exhibit a synthetic-petite phenotype in combination with ntg1 null mutations that is accompanied by enhanced mtDNA point mutagenesis in the corresponding double-mutant strains. This phenotype was partially rescued by malonic acid, indicating that reactive oxygen species generated by the electron transport chain contribute to mitochondrial dysfunction in abf2 Delta strains. In contrast, when two other genes involved in mtDNA recombination, CCE1 and NUC1, were inactivated a strong synthetic-petite phenotype was not observed, suggesting that the effects mediated by Abf2p and Pif1p are due to novel activities of these proteins other than recombination. These results document the existence of recombination-independent mechanisms in addition to base excision repair to cope with oxidative mtDNA damage in Saccharomyces cerevisiae. Such systems are likely relevant to those operating in human cells where mtDNA recombination is less prevalent, validating yeast as a model system in which to study these important issues.

DNA Damage↗
PubMed2002

Mitochondrial DNA--related mitochondrial dysfunction in neurodegenerative diseases.

Mitochondrial dysfunction occurs in several late-onset neurodegenerative diseases. Determining its origin and significance may provide insight into the pathogeneses of these disorders. Regarding origin, one hypothesis proposes mitochondrial dysfunction is driven by mitochondrial DNA (mtDNA) aberration. This hypothesis is primarily supported by data from studies of cytoplasmic hybrid (cybrid) cell lines, which facilitate the study of mitochondrial genotype-phenotype relationships. In cybrid cell lines in which mtDNA from persons with certain neurodegenerative diseases is assessed, mitochondrial physiology is altered in ways that are potentially relevant to programmed cell death pathways. Connecting mtDNA-related mitochondrial dysfunction with programmed cell death underscores the crucial if not central role for these organelles in neurodegenerative pathophysiology. This review discusses the cybrid technique and summarizes cybrid data implicating mtDNA-related mitochondrial dysfunction in certain neurodegenerative diseases.

Apoptosis↗