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PubMed1999

Use of cytoplasmic hybrid cell lines for elucidating the role of mitochondrial dysfunction in Alzheimer's disease and Parkinson's disease.

There is substantial evidence of mitochondrial defects in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases (AD and PD). We have probed the molecular implications of mitochondrial dysfunction in these diseases by transferring mitochondria from platelets obtained from disease and control donors into mitochondrial DNA-depleted recipient neuron-based cells (rho 0 cells). This process creates cytoplasmic hybrid (cybrid) cells where the mitochondrial DNA (mtDNA) from the donor is expressed in the nuclear and cellular background of the host rho 0 cell. Differences in phenotype between disease and control groups can thus be attributed to the exogenous mitochondria and mtDNA. Key methodological issues relating to this approach were addressed by demonstrating that recipient rho 0 cells have < 1 mtDNA copy/cell, and that exclusive repopulation with donor mtDNA occurs in cybrid cells. Further, we describe that sampling of heterogeneous cell populations is a valid approach for cybrid analysis. Our studies show that the focal respiratory chain defects reported in platelets of AD and PD cybrids can be recapitulated in AD and PD cybrids. In addition, both AD and PD cybrids display increased oxidative stress and perturbations in calcium homeostasis. These data suggest that the transfer of a mtDNA defect from disease donor platelets is the likely cause of the cybrid biochemical phenotype, and highlight the potential value of these cell lines as cellular disease models.

Alzheimer Disease↗

PubMed2004

Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy.

OBJECTIVES: We investigated the effects of erbB2 inhibition by anti-erbB2 antibody on cardiomyocyte survival and mitochondrial function. BACKGROUND: ErbB2 is an important signal integrator for the epidermal growth factor family of receptor tyrosine kinases. Herceptin, an inhibitory antibody to the erbB2 receptor, is a potent chemotherapeutic but causes cardiac toxicity. METHODS: Primary cultures of neonatal rat ventricular myocytes were exposed to anti-erbB2 antibody (Ab) (7.5 mug/ml) for up to 24 h. Cell viability, mitochondrial function, and apoptosis were measured using multiple complementary techniques. RESULTS: ErbB2 inhibition was associated with a dramatic increase in expression of the pro-apoptotic Bcl-2 family protein Bcl-xS and decreased levels of anti-apoptotic Bcl-xL. There was a time-dependent increase in mitochondrial translocation and oligomerization of bcl-associated protein (BAX), as indicated by 1,6-bismaleimidohexane crosslinking. The BAX oligomerization was associated with cytochrome c release and caspase activation. These alterations induced mitochondrial dysfunction, a loss of mitochondrial membrane potential (psi) (76.9 +/- 2.4 vs. 51.7 +/- 0.1; p < 0.05; n = 4), a 35% decline in adenosine triphosphate levels (p < 0.05), and a loss of redox capacity (0.72 +/- 0.04 vs. 0.64 +/- 0.02; p< 0.01). Restoration of Bcl-xL levels through transactivating regulatory protein-mediated protein transduction prevented the decline in psi mitochondrial reductase activity and cytosolic adenosine triphosphate. CONCLUSIONS: Anti-erbB2 activates the mitochondrial apoptosis pathway through a previously undescribed modulation of Bcl-xL and -xS, causing impairment of mitochondrial function and integrity and disruption of cellular energetics.

Animals↗

PubMed2002

Mitochondrial dysfunction in schizophrenia: a possible linkage to dopamine.

Mitochondria are not only the principal source of high energy intermediates, but play an important role in intracellular calcium buffering, are main producers of reactive oxygen species, and are the source of pro- and antiapoptotic key factors. Moreover, the mitochondria are of a ubiquitous nature and the respiratory chain has a dual genetic basis, i.e. the mitochondrial and the nuclear DNAs. Thus mitochondrial impairment could provide an explanation for the tremendous heterogeneity of clinical and pathological manifestations in schizophrenia. This article reviews several independent lines of evidence that suggest an involvement of mitochondrial dysfunction in schizophrenia. Among them are altered cerebral energy metabolism, mitochondrial hypoplasia, dysfunction of the oxidative phosphorylation system and altered mitochondrial related gene expression. In addition, the interaction between dopamine, a predominant etiological factor in schizophrenia, and mitochondrial respiration is considered as a possible mechanism underlying the hyper- and hypo-activity cycling in schizophrenia. Understanding the role of mitochondria in schizophrenia may encourage novel treatment approaches, the identification of candidate genes and new insights into the pathophysiology and etiology of the disorder.

Animals↗

PubMed1998

Mitochondrial dysfunction in neurodegenerative disorders.

Mutations of mitochondrial DNA (mtDNA) are associated with a wide spectrum of disorders encompassing the myopathies, encephalopathies and cardiomyopathies, in addition to organ specific presentations such as diabetes mellitus and deafness. The pathogenesis of mtDNA mutations is not fully understood although it is assumed that their final common pathway involves impaired oxidative phosphorylation. The identification of a specific respiratory chain defect (complex I deficiency) in Parkinson's disease (PD) 10 years ago focused attention on the aetiological and pathogenetic roles that mitochondria may play in neurodegenerative diseases. There is evidence now emerging that mtDNA abnormalities may determine the complex I defect in a proportion of PD patients and it may prove possible to use biochemical analysis of platelet and cybrid complex I function to identify those that lie within this group. Respiratory chain defects of a different pattern have been identified in Huntington's disease (HD) (complex II/III deficiency) and Friedreich's ataxia (FA) complex I-III deficiency). In both these disorders, the mitochondrial abnormality is secondary to the primary nuclear mutation:CAG repeat in the huntingtin gene in HD, and GAA repeat in the frataxin gene in FA. Nevertheless, it appears that the mitochondrion may be the target of the biochemical defects that are the consequence of these mutations. There is a close and reciprocal relationship between respiratory chain dysfunction and free radical generation, and there is evidence for oxidative stress and damage in PD, HD and FA, which together with the mitochondrial defect may result in cell damage. Impaired oxidative phosphorylation and free radical generation may independently adversely affect the maintenance of mitochondrial transmembrane potential (Deltapsim). A fall in Deltapsim is an early event (preceding nuclear fragmentation) in the apoptotic pathway. It is possible therefore that mitochondrial dysfunction in the neurodegenerative disorders may result in a fall in the apoptotic threshold of neurones which, in some, may be sufficient to induce cell death whilst, in others, additional factors may be required. In any event, mitochondria present an important target for future strategies for 'neuroprotection' to prevent or retard neurodegeneration.

Animals↗

PubMed2006

Developmental regression and mitochondrial dysfunction in a child with autism.

Autistic spectrum disorders can be associated with mitochondrial dysfunction. We present a singleton case of developmental regression and oxidative phosphorylation disorder in a 19-month-old girl. Subtle abnormalities in the serum creatine kinase level, aspartate aminotransferase, and serum bicarbonate led us to perform a muscle biopsy, which showed type I myofiber atrophy, increased lipid content, and reduced cytochrome c oxidase activity. There were marked reductions in enzymatic activities for complex I and III. Complex IV (cytochrome c oxidase) activity was near the 5% confidence level. To determine the frequency of routine laboratory abnormalities in similar patients, we performed a retrospective study including 159 patients with autism (Diagnostic and Statistical Manual of Mental Disorders-IV and Childhood Autism Rating Scale) not previously diagnosed with metabolic disorders and 94 age-matched controls with other neurologic disorders. Aspartate aminotransferase was elevated in 38% of patients with autism compared with 15% of controls (P <.0001). The serum creatine kinase level also was abnormally elevated in 22 (47%) of 47 patients with autism. These data suggest that further metabolic evaluation is indicated in autistic patients and that defects of oxidative phosphorylation might be prevalent.

Aspartate Aminotransferases↗

PubMed2001

Further evidence for mitochondrial dysfunction in progressive supranuclear palsy.

Recent data from our laboratory have identified a role for mitochondrial dysfunction in the pathogenesis of progressive supranuclear palsy (PSP). To extend this finding, we measured key parameters of mitochondrial function in platelet-derived cytoplasmic hybrid (cybrid) cell lines expressing mitochondrial genes from patients with PSP. We observed significant decreases in aconitase activity, cellular ATP levels, and oxygen consumption in PSP cybrids as compared to control cybrids, further suggesting a contributory role of impaired mitochondrial energy metabolism in PSP, possibly due to genetic abnormalities of mitochondrial DNA.

Adenosine Triphosphate↗

PubMed2004

Mitochondrial dysfunction in reproduction.

The mitochondrial genome passes from one generation to the next by way of the egg's cytoplasm, so ordinarily an individual's mitochondrial DNA (mtDNA) is entirely derived from his or her mother. A potential mother has a finite number of eggs, or oocytes, all of which were formed when she herself was still a fetus, many years before she can conceive. The eggs are progressively depleted through childhood and her reproductive years at a much faster rate than is accounted for by ovulation. Up to a decade before the ultimate depletion of ovarian follicles (and hence oocytes) at or soon after menopause, cytoplasmic senility of the remaining eggs leads to physiological sterility; a phenomenon that is suspected of being mitochondrially based and has been termed the oopause. When ovulation and conception occur, oxidative phosphorylation and other mitochondrial functions of the fertilized oocyte are thought to be essential to the early embryo well before it implants in the uterus. The competition between follicles to deliver the oocyte that will be fertilized and which will found a new generation could also be mitochondrially based, but the mechanism remains to be elucidated. Increasing experience with the culture of human embryos in vitro is highlighting the importance of mitochondrial metabolism generally, and the avoidance of excessive generation of reactive oxygen species in particular. Paradoxes abound in the experimental data, however. Although natural selection operates on mitochondria only in females (and in extreme cases through the survival of their offspring), reproductive disturbance from mitochondrial mutations is most obvious in males, who typically have reduced sperm motility. mtDNA point mutations such as T8993G, which is serious enough to cause the death of infants from Leigh disease in the first few years of life, can carry through the female germ line apparently unhindered; yet mtDNA deletions that cause a less severe phenotype, and which typically manifest at a later age, are effectively blocked from transmission to offspring--a phenomenon in accord with early experimental observations that deleted mtDNA species are less common in cleaving embryos than in unselected preovulatory oocytes. A mitochondrial basis for ooplasmic aging has not been convincingly established, but the novel IVF-based practice of micro-aspiration and transfer of ooplasm from younger eggs to older eggs, which includes the transfer of mitochondria, appears in preliminary studies to have some clinical efficacy in rejuvenating fertility in older women.

Journal Article↗

PubMed2006

Free radical scavenging activity of the marine mangrove Rhizophora apiculata bark extract with reference to naphthalene induced mitochondrial dysfunction.

Rhizophora apiculata bark extract was tested for its free radical scavenging activity and protective role against mitochondrial dysfunction in naphthalene stressed rats. Lipid peroxidation activity was increased and activity of mitochondrial enzymes (cytochrome-c-oxidase, NADH-dehydrogenase, alpha-ketoglutarate dehydrogenase and succinate dehydrogenase) and glutathione was decreased in the liver and kidney of rats intoxicated with naphthalene when compared to control rats. Intraperitoneal administration of plant extract significantly reduced the lipid peroxidation, increased the activity of mitochondrial enzymes and increased glutathione to near control levels. These results suggest that the sulfated polysaccharides in R. apiculata play a protective role through their free radical scavenging properties.

Animals↗

PubMed2005

MIDAS/GPP34, a nuclear gene product, regulates total mitochondrial mass in response to mitochondrial dysfunction.

To investigate the regulatory system in mitochondrial biogenesis involving crosstalk between the mitochondria and nucleus, we found a factor named MIDAS (mitochondrial DNA absence sensitive factor) whose expression was enhanced by the absence of mitochondrial DNA (mtDNA). In patients with mitochondrial diseases, MIDAS expression was increased only in dysfunctional muscle fibers. A majority of MIDAS localized to mitochondria with a small fraction in the Golgi apparatus in HeLa cells. To investigate the function of MIDAS, we stably transfected HeLa cells with an expression vector carrying MIDAS cDNA or siRNA. Cells expressing the MIDAS protein and the siRNA constitutively showed an increase and decrease in the total mass of mitochondria, respectively, accompanying the regulation of a mitochondria-specific phospholipid, cardiolipin. In contrast, amounts of the mitochondrial DNA, RNA and proteins did not depend upon MIDAS. Thus, MIDAS is involved in the regulation of mitochondrial lipids, leading to increases of total mitochondrial mass in response to mitochondrial dysfunction.

Cardiolipins↗

PubMed2005

Reorganization of cytoskeleton induced by 5-aminolevulinic acid-mediated photodynamic therapy and its correlation with mitochondrial dysfunction.

BACKGROUND AND OBJECTIVES: This study investigated the early cellular events which occurred after mitochondrial photodamage induced by 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT). STUDY DESIGN/MATERIALS AND METHODS: Subcellular localization of protoporphyrin IX (PpIX) in NIH3T3 cells was studied by confocal microscopy. Mitochondrial damage was assessed by measuring mitochondrial transmembrane potential and ATP contents, and confirmed by characteristic appearance on transmission electron microscopy. Cellular adhesion was measured by the level of resistance to trypsinization. Cytoskeletal studies were performed by fluorescent staining of cytoskeletal components. RESULTS: Following ALA-PDT, mitochondrial damage was found in NIH3T3 cells as judged by the decrease of membrane potential and ATP contents. Mitochondrial photodamage was further confirmed by electron microscopy. Resistance to trypsinization after ALA-PDT was shown to be light dose-dependent. The increase of cellular adhesion after ALA-PDT was correlated with mitochondrial photodamage and reorganization of cytoskeletal components in NIH3T3 cells. CONCLUSIONS: This study has demonstrated that mitochondrial dysfunctions induced by ALA-PDT results in alterations of cellular morphology and cellular adhesion.

Acid Phosphatase↗

PubMed1998

Discontinuous total parenteral nutrition prevents postischemic mitochondrial dysfunction in rat liver.

Although discontinuous total parenteral nutrition (d-TPN) has recently been favored for clinical use over continuous total parenteral nutrition (c-TPN) to ameliorate liver dysfunction, mechanisms for the protection against postoperative liver dysfunction remain unknown. This study aimed to examine differences in mitochondrial function in d-TPN- and c-TPN-pretreated livers during ischemia-reperfusion. Rat livers pretreated with d-TPN or c-TPN were perfused with Krebs-Ringer buffer and were exposed to 25% low-flow hypoxia followed by reperfusion. Intrahepatic mitochondrial membrane potential (triangle up) and cell viability were assessed by dual-color digital microfluorography using rhodamine 123 (Rh123) and propidium iodide (PI), respectively. In response to hypoxia, livers pretreated with c-TPN, d-TPN, and an ordinary chow diet exhibited a significant triangle up reduction among the entire lobules. Upon reperfusion, the regional triangle up values further decreased in the c-TPN liver, whereas those in the d-TPN-treated or chow-treated livers displayed a rapid recovery toward the control levels. The severity of cell injury did not differ among the groups, showing that the reperfusion-induced triangle up drop in the c-TPN-pretreated liver is not a consequence of cell injury. Differences in the triangle up drop among the groups appear to occur irrespective of those in the glycogen storage, because the livers undergoing d-TPN display a marked triangle up recovery even when reperfused at the end of a fasted state. These results indicate that c-TPN, but not d-TPN, jeopardizes mitochondrial re-energization and suggest that a circadian pattern of the TPN serves as a potentially beneficial strategy to reduce the risk of postischemic mitochondrial dysfunction in the liver.

Animals↗

PubMed2006

Hypomorphic mutation of PGC-1beta causes mitochondrial dysfunction and liver insulin resistance.

PGC-1beta is a transcriptional coactivator that potently stimulates mitochondrial biogenesis and respiration of cells. Here, we have generated mice lacking exons 3 to 4 of the Pgc-1beta gene (Pgc-1beta(E3,4-/E3,4-) mice). These mice express a mutant protein that has reduced coactivation activity on a subset of transcription factors, including ERRalpha, a major target of PGC-1beta in the induction of mitochondrial gene expression. The mutant mice have reduced expression of OXPHOS genes and mitochondrial dysfunction in liver and skeletal muscle as well as elevated liver triglycerides. Euglycemic-hyperinsulinemic clamp and insulin signaling studies show that PGC-1beta mutant mice have normal skeletal muscle response to insulin but have hepatic insulin resistance. These results demonstrate that PGC-1beta is required for normal expression of OXPHOS genes and mitochondrial function in liver and skeletal muscle. Importantly, these abnormalities do not cause insulin resistance in skeletal muscle but cause substantially reduced insulin action in the liver.

Animals↗

PubMed1994

Acetylsalicylate (ASA)-induced mitochondrial dysfunction and its potentiation by Ca2+.

Although it has been suggested that acetylsalicylate (ASA)-induced mitochondrial dysfunction plays an important role in the pathogenesis of Reye's syndrome, administration of ASA alone does not cause this syndrome in therapeutic doses. We noted, however, that Ca2+ plays important roles in the regulation of cellular functions. ASA at concentrations of 250 microM or less, which had little effect on succinate-linked respiration, impaired Ca2+ accumulation in liver mitochondria by causing an increase in Ca2+ release. ASA plus Ca2+, which in concentrations of 150 microM or less alone had little effect on mitochondrial respiration, inhibited state 3 respiration and dinitrophenol-induced uncoupling of respiration. In addition, ASA plus Ca2+ increased state 4 respiration and ATPase activity. These results indicate that ASA plus Ca2+ impaired mitochondrial ATP synthesis, and suggest that ASA and ASA-induced Ca2+ increases in cytosol form a vicious circle of effects. Furthermore, oral administration of ASA (150 mg/kg for 5 days running) to rats did not affect mitochondrial structure or liver function, but resulted in aberrations of mitochondrial respiration. These results suggest that even therapeutic doses of ASA may induce alteration in mitochondrial function.

Adenosine Triphosphatases↗

PubMed2003

Role of mitochondrial dysfunction in hydrogen peroxide-induced apoptosis of intestinal epithelial cells.

AIM: To study the role of mitochondrial dysfunction in hydrogen peroxide-induced apoptosis of intestinal epithelial cells. METHODS: Hydrogen peroxide-induced apoptosis of human intestinal epithelial cell line SW-480 was established. Cell apoptosis was determined by Annexin-V and PI double-stained flow cytometry and DNA gel electrophoresis. Morphological changes were examined with light and electron microscopy. For other observations, mitochondrial function, cytochrome c release, mitochondrial translocation and membrane potential were determined simultaneously. RESULTS: Percentage of apoptotic cells induced with 400 micro mol/L hydrogen peroxide increased significantly at l h or 3 h after stimulation and recovered rapidly. Meanwhile percentage of apoptotic cells induced with 4 mmol/L hydrogen peroxide increased with time. In accordance with these changes, we observed decreased mitochondrial function in 400 micro mol/L H2O2-stimualted cells at 1 h or 3 h and in 4 mmol/L H2O2-stimualted cells at times examined. Correspondingly, swelling cristae and vacuole-like mitochondria were noted. Release of cytochrome c, decreased mitochondrial membrane potential and mitochondrial translocation were also found to be the early signs of apoptosis. CONCLUSION: Dysfunctional mitochondria play a role in the apoptosis of SW-480 cell line induced by hydrogen peroxide.

Apoptosis↗

PubMed2006

Mitochondrial dysfunction in sporadic and genetic Alzheimer's disease.

Increasing evidence suggests an important role of mitochondrial dysfunction in the pathogenesis of many common age-related neurodegenerative diseases, including Alzheimer's disease (AD). AD is the most common neurodegenerative disorder characterized by dementia, memory loss, neuronal apoptosis and eventually death of the affected individuals. AD is characterized by two pathologic hallmark lesions that consist of extracellular plaques of amyloid-beta peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated microtubular protein tau. Even though the idea that amyloid beta peptide accumulation is the primary event in the pathogenesis of Alzheimer's disease has become the leading hypothesis, the causal link between aberrant amyloid precursor protein and tau alterations in this type of dementia remains controversial.

Aging↗

PubMed1996

Relationship between mitochondrial dysfunction and toxicity of propyl gallate in isolated rat hepatocytes.

The relationship between cytotoxicity and mitochondrial dysfunction caused by propyl gallate (PG) has been studied in hepatocytes freshly prepared from fasted rats. Hepatocytes isolated from fasted (18 h) rats were significantly more susceptible to the toxicity of PG than hepatocytes from fed rats. The addition of fructose (15 mM), an alternative carbohydrate source, to hepatocyte suspensions resulted in the prevention of PG (1 mM)-induced cell killing accompanied by decrease in intracellular ATP loss during a 3 h-incubation period. Despite this, fructose did not completely prevent an abrupt loss of intracellular glutathione caused by PG, but effectively inhibited the loss of protein thiol levels. Fructose elicited a concentration (0.5-20mM)-dependent protection against the cytotoxicity of 1.5 mM PG. The incubation of hepatocytes with sodium azide (4 mM), an inhibitor of oxidative phosphorylation, enhanced the toxicity induced by PG (1 mM), but coincubation with fructose delayed the onset of toxicity. Neither azide alone nor fructose plus azide did affect the cell viability during the incubation period. Furthermore, the addition of 2 mM salicylamide, nontoxic to hepatocytes during the incubation period, enhanced PG (1 mM)-induced cytotoxicity and decreased the loss of free PG. These results indicate that the onset of cytotoxicity caused by PG may depend on the intracellular energy status and that mitochondria are critical target for the compound. In addition, the toxicity caused by the inhibition of mitochondrial ATP synthesis is related to the concentration of PG remaining in cell suspensions.

Adenosine Triphosphate↗

PubMed2004

Mitochondrial dysfunction and heart disease.

Several inherited and acquired disorders of mitochondria lead to defects in cardiac function as reflected in exercise intolerance, arrhythmias and heart failure. Manifestations of mitochondrial dysfunction is reflected in the abnormal mitochondrial proliferation, structure and ultimately as cytochrome C-induced apoptosis. How these defects are associated with disordered cytosolic events including SR calcium release and transcription has suggested a cross talk of mitochondria and cytosolic events that drive cardiomyocytes dysfunction.

Journal Article↗

PubMed2006

Depletion of adenine nucleotide translocator protein in heart mitochondria from doxorubicin-treated rats--relevance for mitochondrial dysfunction.

Doxorubicin (DOX) is a highly effective treatment for several forms of cancer. However, DOX induces a cumulative and dose-dependent cardiomyopathy that has been ascribed to redox-cycling of the molecule on the mitochondrial complex I generating in the process increased oxidative stress. Mitochondrial dysfunction, including induction of the mitochondrial permeability transition (MPT) and inhibition of mitochondrial respiration have been implicated as major determinants in the pathogenesis of DOX cardiotoxicity. The adenine nucleotide translocator (ANT) has been suggested to be a principal component of the MPT pore and a possible target for DOX-induced cardiotoxicity. Nonetheless, no definitive evidence has been presented showing that altered ANT activity is due to decreased amount of the protein. By using carboxyatractyloside as a specific modulator of ANT activity and Western blotting, we observed that following DOX treatment in rats: (1) the amount of "functional ANT" that contributes to cardiac mitochondrial respiration with different substrates is reduced, (2) titrations with carboxyatracyloside revealed a lower threshold for MPT induction and most importantly, (3) a specific decrease in the amount of the ANT protein. This study identifies the ANT as one important target for DOX-induced cardiac toxicity and correlates the decrease in ANT protein concentration with inhibition of mitochondrial respiration and increased ability to form or at least regulate MPT pores.

Adenine Nucleotide Translocator 1↗