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PubMed2004

An evolutionary perspective on pathogenic mtDNA mutations: haplogroup associations of clinical disorders.

More than 75 human diseases have been associated with mitochondrial dysfunction, and many of these are directly caused by overtly pathogenic mutations in the mitochondrial genome (mtDNA). In addition, there have been a number of reports that posit a different, subtler role for mtDNA substitutions in the disease process. As we review here, mtDNA evolution has resulted in the distribution of sequences into continent-specific haplogroups, which are defined by a relatively small number of polymorphisms. Thus, mtDNA sequences can be assigned to European, African, or Asian/Native American haplogroups. There are numerous reports that various diseases are haplogroup-associated, and it has been suggested that some of these haplogroup-associated polymorphisms act as risk factors in these disorders. It has also been suggested that there are haplogroup-associations for aging. As we note here, however, such associations have usually been observed only in single studies and it is difficult to draw broad conclusions on the basis of the available evidence. At a minimum, we suggest that, a haplogroup-group association must be detected in multiple subpopulations or in a large, carefully controlled population survey.

Journal Article↗
PubMed2002

Mitochondrial involvement in amyotrophic lateral sclerosis.

The causes of motor neuron death in amyotrophic lateral sclerosis (ALS) are so far unknown. The involvement of mitochondria in the disease was initially suggested by ultrastructural studies. More recently these observations have been supported by studies of mitochondrial function in ALS. Alterations in the activity of complexes which make up the mitochondrial electron transport chain have been recorded as well as mutations in the mitochondrial genome. The calcium buffering function of the mitochondria may also be affected in the disease. This review will discuss how mitochondrial dysfunction could be of relevance in ALS and the evidence that an alteration of mitochondrial function is a feature of the disease. The way in which the involvement of mitochondria fits with other aetiological hypotheses for ALS will also be discussed.

Amyotrophic Lateral Sclerosis↗
PubMed2003

Expression of dengue ApoptoM sequence results in disruption of mitochondrial potential and caspase activation.

Apoptotic cell death has been involved as a cytopathologic mechanism in response to dengue (DEN) virus infection. Little information exists about how DEN virus replication triggers apoptosis in infected cells. We reported that a nine-residue sequence of the DEN M protein referred to as ApoptoM has proapoptotic properties in transformed and tumor cells of various origins. The aim of the present study was to investigate whether ApoptoM-induced apoptosis is associated to mitochondrial dysfunction and requires caspase activation. Intracellular expression of ApoptoM provokes the disruption of the mitochondrial transmembrane potential without subsequent generation of reactive oxygen species. We showed that ApoptoM-induced apoptosis involves the activation of a caspase-like protease pathway. Caspase-3 like activity was detected in ApoptoM-expressing cells. However, there was no role for caspase-9 in ApoptoM-mediated cell death. Our data suggest that a particular mitochondrion-dependent apoptotic pathway may be involved in induction of apoptosis by ApoptoM.

Amino Acid Chloromethyl Ketones↗
PubMed1996

Clinical spectrum of mitochondrial diseases.

Mitochondrial diseases include myopathies and multisystem disorders. They are characterized by morphologic and biochemical abnormalities of mitochondria. Their genetic characteristics-maternal inheritance, heteroplasmy, mitotic segregation, and threshold effect-are unique. The clinical phenotypes are considerably heterogeneous, but the clinical presentation in many cases is characteristic or suggestive. We review the clinical features of the most prevalent mitochondrial encephalomyopathy syndromes, their molecular genetic basis, isolated clinical symptoms, and uncommon presentations. Molecular genetic diagnosis is available for the common syndromes and has revolutionized their diagnosis. Future therapeutic advances, based on the precise genetic etiology, are anticipated. Mitochondrial dysfunction may be a more frequent pathogenetic mechanism than the prevalence of the classic mitochondrial syndromes would indicate, as there is an association between the accumulation of mitochondrial DNA mutations in postmitotic tissues and neurologic and systemic degenerative diseases.

Animals↗
PubMed2003

Hypoxia potentiates nitric oxide-mediated apoptosis in endothelial cells via peroxynitrite-induced activation of mitochondria-dependent and -independent pathways.

Nitric oxide (NO*) at low concentrations is cytoprotective for endothelial cells; however, elevated concentrations of NO* (> or =1 micromol/liter), as may be achieved during inflammatory states, can induce apoptosis and cell death. Hypoxia is associated with tissue inflammation and ischemia and, therefore, may modulate the effects of NO* on endothelial function. To examine the influence of hypoxia on NO*-mediated apoptosis, we exposed bovine aortic endothelial cells (BAEC) to (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) amino]diazen-1-ium-1,2-diolate (diethylenetriamine NONOate, DETA-NO) (1 mmol/liter) under normoxic or hypoxic conditions (pO2 = 35 mm of Hg) and measured the indices of apoptotic cell death. BAEC treated with DETA-NO under normoxic conditions demonstrated increased levels of histone-associated DNA fragments, which was confirmed by terminal dUTP nick-end labeling assay, and hypoxic conditions augmented this response. To determine whether mitochondrial dysfunction was one mechanism by which NO* initiated apoptosis under hypoxic conditions, we evaluated mitochondrial membrane potential in (Psim). Exposure to DETA-NO resulted in a decrease in Psim and concomitant release of cytochrome c and caspase-9 activation, which were enhanced by hypoxia. By utilizing Rho0 BAEC (Rho0-EC), which lack functional mitochondria, we demonstrated that dissipation of Psim was associated with increased reactive oxygen species generation and peroxynitrite formation. Moreover, in Rho0-EC we identified activation of caspase-8 as part of the mitochondrial-independent pathway of apoptosis. To establish that peroxynitrite mediated mitochondrial damage and apoptosis, we treated BAEC and Rho0-EC with the peroxynitrite scavenger uric acid and found that the indices of apoptosis were decreased significantly. These findings confirm that high flux of NO* under hypoxic conditions promotes cell death via mitochondrial damage and mitochondrial-independent mechanisms by peroxynitrite.

Animals↗
PubMed2006

A novel mechanism of action of methyl-2-cyano-3,12 dioxoolean-1,9 diene-28-oate: direct permeabilization of the inner mitochondrial membrane to inhibit electron transport and induce apoptosis.

Methyl-2-cyano-3,12 dioxoolean-1,9 diene-28-oate (CDDO-Me) is a synthetic oleanolic acid derivative that displays antitumorigenic and anti-inflammatory activities, and we have previously reported that this agent potently activates the intrinsic apoptotic pathway in leukemia cells. In this study, we demonstrate that mitochondrial dysfunction induced by CDDO-Me is mediated by direct permeabilization of the inner mitochondrial membrane, which results in the rapid depletion of mitochondrial glutathione (GSXm), loss of cardiolipin, and inhibition of mitochondrial respiration. More importantly, we demonstrate that in addition to activating the intrinsic apoptotic pathway, the mitochondrial effects of CDDO-Me may mediate its anti-inflammatory activity by modulating the generation of superoxide anion (O2*). It is noteworthy that CDDO-Me did not increase the generation of O2* and pretreatment of leukemia cells with CDDO-Me prevented the increase of this reactive oxygen species elicited by inhibition of complex I or III in the absence of de novo protein synthesis. CDDO-Me, but not other inhibitors of respiration, induced a time- and dose-dependent, cyclosporin A-independent permeability transition (PT) of isolated mitochondria that was sensitive to sulfhydryl antioxidants but not to EDTA. PT induced by CDDO-Me and Ca2+ was accompanied by loss of GSXm, suggesting that the increased permeability of the inner mitochondrial membrane facilitates the loss of this antioxidant. Finally, transmission electron microscopy revealed that CDDO-Me rapidly induced caspase-independent mitochondrial swelling and loss of inner membrane structure before the release of cytochrome c. Taken together, our results indicate that CDDO-Me is a novel mitochondriotoxic agent that induces apoptosis and inhibits mitochondrial electron transport via perturbations in inner mitochondrial membrane integrity.

Apoptosis↗
PubMed2002

Mitochondrial abnormalities and oxidative imbalance in neurodegenerative disease.

An increasing body of evidence now suggests the involvement of mitochondrial abnormalities in the etiology of neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer disease. In this Perspective, we describe a recent study that shows that treatment of human patients with the antioxidant coenzyme Q(10'), which functions in concert with certain mitochondrial enzymes, reduced the worsening of symptoms associated with PD. These findings are consistent with the hypothesis that mitochondrial dysfunction plays a role in the pathogenesis of PD and that treatments that target mitochondrial biochemistry might ameliorate the functional decline observed in patients suffering from PD.

Coenzymes↗
PubMed2006

Mitochondrial function in vivo evaluated by NADH fluorescence: from animal models to human studies.

Normal mitochondrial function is a critical factor in maintaining cellular homeostasis in various organs of the body. Due to the involvement of mitochondrial dysfunction in many pathological states, the real-time in vivo monitoring of the mitochondrial metabolic state is crucially important. This type of monitoring in animal models as well as in patients provides real-time data that can help interpret experimental results or optimize patient treatment. The goals of the present review are the following: 1) to provide an historical overview of NADH fluorescence monitoring and its physiological significance; 2) to present the solid scientific ground underlying NADH fluorescence measurements based on published materials; 3) to provide the reader with basic information on the methodologies used in the past and the current state of the art fluorometers; and 4) to clarify the various factors affecting monitored signals, including artifacts. The large numbers of publications by different groups testify to the valuable information gathered in various experimental conditions. The monitoring of NADH levels in the tissue provides the most important information on the metabolic state of the mitochondria in terms of energy production and intracellular oxygen levels. Although NADH signals are not calibrated in absolute units, their trend monitoring is important for the interpretation of physiological or pathological situations. To understand tissue function better, the multiparametric approach has been developed where NADH serves as the key parameter. The development of new light sources in UV and visible spectra has led to the development of small compact units applicable in clinical conditions for better diagnosis of patients.

Animals↗
PubMed2002

Reduced activity of mtTFA decreases the transcription in mitochondria isolated from diabetic rat heart.

To evaluate abnormalities in the mitochondrial transcription factor A (mtTFA) function as a cause of mitochondrial dysfunction in diabetes, we measured the mRNA contents of the proteins consisting of the mitochondrial respiratory chain as well as transcriptional and translational activities in the mitochondria isolated from controls and streptozotocin-induced diabetic rat hearts. Using Northern blot analysis, we found 40% reduced mRNA contents of mitochondrial-encoded cytochrome b and ATP synthase subunit 6 in diabetic rat hearts compared with control rats (P < 0.05). These abnormalities were completely recovered by insulin treatment. Furthermore, the mitochondrial activities of transcription and translation were decreased significantly in mitochondria isolated from diabetic rats by 60% (P < 0.01) and 71% (P < 0.01), respectively, compared with control rats. The insulin treatment also completely normalized these abnormalities in diabetic rats. Consistently, gel retardation assay showed a reduced binding of mtTFA to the D-loop of mitochondrial DNA in diabetic rats, although there was no difference in the mtTFA mRNA and protein content between the two groups. On the basis of these findings, a reduced binding activity of mtTFA to the D-loop region in the hearts of diabetic rats may contribute to the decreased mitochondrial protein synthesis.

Animals↗
PubMed1994

Multiple symmetric lipomatosis: abnormalities in complex IV and multiple deletions in mitochondrial DNA.

Multiple symmetric lipomatosis (MSL) is a rare disorder of middle life characterized by large nonencapsulated lipomas distributed around the neck, shoulders, and other axial regions. Neurologic involvement, particularly peripheral neuropathy, is frequent. The pathogenesis of the syndrome is still unknown, but ragged-red fibers are occasionally present in muscle of affected patients, suggesting a mitochondrial abnormality. We studied 11 unrelated patients with MSL by means of neurophysiology, muscle morphology, muscle biochemistry, Southern blot, and PCR analysis of mitochondrial DNA. All patients were men aged 41 to 63 years. Clinical or electrophysiologic signs of a sensorimotor polyneuropathy were present in nine patients, eight of whom had a history of alcoholism. In muscle biopsy specimens, the most prominent feature was pathologic subsarcolemmal aggregates of mitochondria. Biochemical analysis of respiratory chain enzymes revealed a moderate but significant decrease of cytochrome c oxidase activity as compared with age-matched controls. In one patient, Southern blot analysis showed multiple deletions of mitochondrial DNA. We conclude that mitochondrial dysfunction is common in MSL and may be based on identifiable defects in the mitochondrial genome.

Adult↗
PubMed1999

Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation.

OBJECTIVE: To investigate a family with maternally inherited, adult-onset multisystem degeneration including prominent parkinsonism to determine whether clinical features can result from a mitochondrial DNA (mtDNA) mutation. The parkinsonism was levodopa responsive and was associated with the loss of pigmented neurons in the substantia nigra in at least one patient. BACKGROUND: Mitochondrial dysfunction is hypothesized to play a role in late-onset neurodegenerative diseases including PD and AD. Mitochondrial genetic mutations are hypothesized to account for these defects, but attempts to identify specific mtDNA mutations have been inconclusive. METHODS: Clinical examinations, DNA sequencing, and restriction digestion and biochemical analyses were performed. RESULTS: Maternal relatives harbor a G-to-A missense mutation, heteroplasmic in some patients, at nucleotide position 11778 of the mitochondrial ND4 gene of complex I that converts a highly conserved arginine to a histidine. Sequencing of the entire mitochondrial genome in an affected family member reveals no other mutations likely to be pathogenic. This mutation has been identified previously only in families with Leber's hereditary optic neuropathy-a disorder also linked to complex I dysfunction but usually limited clinically to optic atrophy. CONCLUSIONS: These data reveal previously unsuspected clinical heterogeneity of the G11778A mutation, and suggest that an inherited mtDNA mutation can contribute to the development of adult-onset parkinsonism and multisystem degeneration.

Base Sequence↗
PubMed1997

Mitochondrial tRNA(Cys) gene mutation (A5814G): a second family with mitochondrial encephalopathy.

We report an Italian family with maternally inherited encephalomyopathy including progressive external ophthalmoplegia, seizures, and neurophysiological evidence of brainstem dysfunction. Mitochondrial DNA analysis showed a heteroplasmic point mutation at position 5814 in the tRNA gene for cysteine (A5814G), previously reported in a 5-year-old girl of Portuguese origin. The mutation was very abundant (> 95%) in both muscle and blood from the proposita and was present in lower proportions (average 85 +/- 6%) in blood from three less severely affected maternal relatives. This observation confirms pathogenicity for the A5814G mutation.

Adult↗
PubMed2001

46,XX gonadal dysgenesis, short stature, and recurrent metabolic acidosis in two sisters.

Gonadal (ovarian) dysgenesis in 46,XX individuals is genetically heterogeneous. We report on two sisters who, in addition to primary ovarian failure, have marked short stature and recurrent episodes of dehydration with metabolic acidosis. Studies performed during one of these episodes suggested mitochondrial dysfunction; however, results of biochemical analysis of electron transport chain activity in skeletal muscle and mitochondrial DNA studies were normal. We discuss the phenotype in relation to previously described conditions of 46,XX gonadal dysgenesis. We suggest this constellation of findings represents a new syndrome.

Acidosis↗
PubMed1997

Bcl-2 completely blocks Fas-mediated apoptosis in mtDNA-depleted HeLa cells.

Bcl-2 inhibits apoptosis induced by a variety of death stimuli but does not completely inhibit Fas-mediated apoptosis. We have previously shown that a HeLa-derived cell line lacking mitochondrial DNA (mtDNA) expresses Fas at a high level and apoptosis is easily induced using a low concentration of an anti-Fas antibody. In this study, overexpression of Bcl-2 in the mtDNA-less cells completely blocked Fas-mediated apoptosis, and this was not due to a depression of the enhanced Fas expression. These findings suggest that the Fas-mediated apoptotic pathway is directly linked to Bcl-2 protection in the cells with an accompanying mitochondrial dysfunction.

Antibodies↗
PubMed2004

Coenzyme Q10 serum levels in Huntington's disease.

Mitochondrial dysfunction contributes to the neurodegenerative process in Huntington's disease (HD). Coenzyme Q10 (CoQ10) enhances mitochondrial complex I activity and may therefore provide a therapeutic benefit in HD. We compared serum CoQ10 levels of previously untreated-and treated HD patients with those of healthy controls. CoQ10 did not significantly (ANCOVA F(dF 2, dF 55) = 2.57; p=0.086) differ between all three groups. However, the post hoc analysis showed no significant (p = 0.4) difference between treated HD patients ([CoQ10]: 88.12 [mean]+/-24.44 [SD], [range] 48.75-146.32 [pg/million platelets]) and controls (93.71+/-20.72, 65.31-157.94), however previously untreated HD patients (70.10+/-21.12, 38.67-106.14) had marked (p = 0.051) lower CoQ10 results than treated HD patients and controls (p = 0.017). Our results support that CoQ10 supplementation in HD patients may reduce impaired mitochondrial function in HD.

Adult↗
PubMed2005

Nuclear MRP genes and mitochondrial disease.

The ancestral mitochondrial ribosome (70S) underwent major structural remodeling during the evolution of mammalian mitochondrial ribosomes (55S). Despite the loss of nearly half their RNA, 55S ribosomes are actually larger than bacterial ribosomes because of all the extra proteins they contain. Typical of mammalian mitochondrial ribosomes, the human mitochondrial ribosome is one of the most protein-rich ribosomes, containing several new proteins. One of the new proteins is a novel GTP binding protein, DAP3, that has been implicated in apoptosis. Except for DAP3, the locations of the individual new proteins in the ribosome are unknown. All of the MRPs are encoded by nuclear genes. Mutations or deficiencies of ribosome assembly proteins or other essential proteins are candidates for mitochondrial disease, since the mitochondrial ribosome translates mRNAs for the 13 essential components of the oxidative phosphorylation system. Several of the MRP genes map to loci associated with disorders consistent with impaired oxidative phosphorylation, such as Leigh Syndrome, multiple mitochondrial dysfunctions, and non-syndromic hearing loss. This manuscript reviews the distinctive properties of human mitochondrial ribosomes and ribosomal proteins, and the correlation of MRP3 gene locations with loci associated with disorders of energy metabolism, and provides localization information for one of the unusual proteins contained in human mitochondrial ribosomes, MRPS29.

Chromosome Mapping↗
PubMed2006

4-Hydroxynonenal induces vascular smooth muscle cell apoptosis through mitochondrial generation of reactive oxygen species.

4-Hydroxynonenal (HNE), an end-product of membrane lipid peroxidation, has been suggested to mediate a number of oxidative stress-linked pathological events such as cellular apoptosis. However, little is known about the signals by which HNE induces vascular smooth muscle cell (VSMC) apoptosis. To elucidate the mechanism(s) involved in HNE-induced VSMC apoptosis, we investigated the importance of mitochondria as a potential source for reactive oxygen species (ROS). Exposure of VSMC to HNE (1-30 microM) showed an augmented apoptotic changes in a concentration-dependent manner in association with an increased production of ROS, both of which were significantly attenuated by mitochondrial inhibitors such as rotenone (0.1 microM) and stigmatellin (0.1 microM), but not affected by other oxidase inhibitors involving NADPH oxidase, xanthine oxidase and cyclooxygenase. In connection with these results, HNE-induced ROS generation was not observed in mitochondrial function-deficient (rho 0) VSMC. Taken together, these results suggest that mitochondrial dysfunction plays a key role in mediating HNE-induced VSMC apoptosis through an increased mitochondrial production of ROS.

Aldehydes↗
PubMed2000

Increased striatal dopamine turnover following acute administration of rotenone to mice.

Because of the potential role of mitochondrial dysfunction in nigrostriatal degeneration in Parkinson's disease, the effects of rotenone (an inhibitor of mitochondrial NADH dehydrogenase and a naturally occurring toxicant) on the levels of striatal dopamine (DA) and DA metabolites were evaluated after acute and subchronic administration to mice. Systemic acute treatment with relatively high doses of rotenone did not affect DA concentration, but caused a significant increase in both DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). DOPAC and HVA changes were measured at 1 day and were reversed within 1 week, paralleling the time course of rotenone-induced increase in striatal lactate levels. Subchronic administration with a relatively mild dose of rotenone did not significantly alter the striatal levels of DA and DOPAC, while it slightly reduced HVA concentration. No neurochemical signs of dopaminergic damage were seen when mice were co-exposed to rotenone and diethyldithiocarbamate, a compound known to enhance nigrostriatal injury caused by the neurotoxicant 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP). Also, rotenone did not cause additional injury to animals previously lesioned by MPTP. Taken together, data indicate that rotenone is not capable of causing overt dopaminergic toxicity under the testing paradigms used in this study. Rather, an increase in DA turnover, as indicated by a higher (DOPAC+HVA)/DA ratio, seems to be associated to rotenone-induced striatal energy impairment.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗