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PubMed1989

Mitochondrial encephalomyopathies.

Increasingly numerous studies are being devoted to mitochondrial diseases, notably those which involve the neuromuscular system. Our knowledge and understanding of these diseases is progressing rapidly. We owe to Luft et al. (1962) the first description of this type of diseases. Their patient, a woman, presented with clinical symptoms suggestive of mitochondrial dysfunction, major histological abnormalities of skeletal muscle mitochondria and defective oxidative phosphorylation coupling clearly demonstrated in mitochondria isolated from muscle. This clinical, histological and biochemical triad led to the definition of mitochondrial myopathies. Subsequently, the triad was seldom encountered, and most mitochondrial myopathies were primarily defined by the presence of morphological abnormalities of muscle mitochondria. This review deals with the morphological, clinical, biochemical and genetic aspects of mitochondrial encephalomyopathies. The various morphological abnormalities of mitochondria are described. These are not specific of any particular disease. They may be present in some non-mitochondrial diseases and may be lacking in diseases due to specific defects of mitochondrial enzymes (e.g. carnitine palmityl-transferase or pyruvate dehydrogenase). The clinical classification of mitochondrial encephalomyopathies is discussed. There are two main schools of thought: the "lumpers" do not recognize specific syndromes within the spectrum of mitochondrial "cytopathies", the "splitters" try to identify specific syndromes while recognizing the existence of borderline cases. The following syndromes are described: chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), MERRF syndrome (myoclonic epilepsy with ragged-red fibers), MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) and Leigh and Alpers syndromes. The biochemical classification comprises five types of abnormalities: defects of transport through the mitochondrial membrane, of substrate utilization, of Krebs' cycle, of oxidative phosphorylation and of various complexes of the respiratory chain. The clinical pictures corresponding to these defects are briefly described. The genetic aspects of these diseases are especially interesting because mitochondria have their own genome coding for thirteen proteins, all of them belonging to the respiratory chain. Genetic mitochondrial diseases may result from alterations of the nuclear genome, which are transmitted by mendelian inheritance, but they may also be due to alterations of the mitochondrial genome and transmitted by non-mandelian "maternal" heredity. A few examples are discussed, including Leber's optic atrophy and MERRF syndrome. (ABSTRACT TRUNCATED AT 400 WORDS)

Brain Diseases, Metabolic↗

PubMed1995

[Chronic fatigue syndrome--a review of the literature].

Chronic fatigue syndrome is a clinical condition characterized by abnormal fatigue, subfebrile body temperature, sore throat, lymphadenopathy, arthralgia, myalgia and neuropsychiatric symptoms. Typically, the syndrome develops after a flu-like illness and is markedly exacerbated by exercise. The etiology is unknown and there is no single diagnostic test. The patients may have cognitive dysfunction, immunological and endocrinological abnormalities and abnormal mitochondria. Magnetic resonance imaging scans may show increased uptake of signals in the brain, and single photon emission computerized tomography reveals regional hypoperfusion of the brain. The author discusses similarities and distinctions between the syndrome and depression.

Fatigue Syndrome, Chronic↗

PubMed2004

Metabolism of 4-hydroxy-trans-2-nonenal by central nervous system mitochondria is dependent on age and NAD+ availability.

Lipid peroxidation and mitochondrial dysfunction are associated with multiple neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. 4-Hydroxy-trans-2-nonenal (HNE) is a major, neurotoxic product of lipid peroxidation whose levels are elevated in these diseases. Previous data from this laboratory demonstrate that mitochondria play an important role in the detoxification of HNE particularly through the oxidation of HNE to 4-hydroxy-trans-2-nonenoate (HNEAcid). In this work, we examined the disposition of HNE when incubated with intact, well-coupled, rat brain mitochondria. Our results demonstrated that HNE loss occurred in a time- and concentration-dependent, saturable manner with a K(M) of 28.0 +/- 11.8 microM HNE and a V(Max) of 10.0 +/- 1.7 nmol/min/mg. HNEAcid formation occurred in a saturable manner with a K(M) of 25.3 +/- 6.3 microM HNE and a V(Max) of 4.4 +/- 0.43 nmol/min/mg. The formation of HNE-glutathione adducts and HNE-protein adducts comprised only a small percentage of HNE consumption. HNE metabolism was significantly diminished in rat brain mitochondria isolated from older animals. We then tested the hypothesis that the mitochondrial NADH/NAD(+) ratio regulated matrix aldehyde dehydrogenase activity. Our results demonstrate that HNE oxidation was significantly inhibited to a greater extent with pyruvate and malate as substrates vs succinate. Complex I inhibition with respiratory substrates further blocked HNE detoxification. Rotenone (100 nM) inhibited respiration by 15% whereas HNEAcid formation was decreased to 72% of control levels. These results demonstrate that in situ mitochondrial aldehyde detoxification is affected by decrements in NAD(+) availability and complex I activity.

Acetaldehyde↗

PubMedDate not supplied

Metabolic stages, mitochondria and calcium in hypoxic/ischemic brain damage.

Cerebral hypoxia/ischemia leads to mitochondrial dysfunction due to lack of oxygen leaving the glycolytic metabolism as a main pathway for ATP production. Inhibition of mitochondrial respiration thus triggers generation of lactate and hydrogen ions (H+), and furthermore dramatically reduces ATP generation leading to disregulation of cellular ion metabolism with subsequent intracellular calcium accumulation. Upon reperfusion, when mitochondrial dysfunction is (at least partially) reversed by restoring cerebral oxygen supply, bioenergetic metabolism recovers and brain cells are able to re-institute their normal ionic homeostatic mechanisms. However, the initial restoration of normal mitochondrial function may be only transient and followed by a secondary, delayed perturbation of mitochondrial respiratory performance seen as a decrease in cellular ATP levels and known as "secondary energy failure". There have been several mechanisms considered responsible for delayed post-ischemic mitochondrial failure, the mitochondrial permeability transition (MPT) being one that is considered important. Although the amount of calcium available during early reperfusion in vivo is limited, relative to the amount needed to trigger the MPT in vitro; the additional intracellular conditions (of acidosis, high phosphate, and low adenine nucleotideae levels) prevailing during reperfusion, favor MPT pore opening in vivo. Furthermore, the cellular redistribution and/or changes in the intracellular levels of pro-apoptotic proteins can alter mitochondrial function and initiate apoptotic cell death. Thus, mitochondria seem play an important role in orchestrating cell death mechanisms following hypoxia/ischemia. However, it is still not clear which are the key mechanisms that cause mitochondrial dysfunction and lead ultimately to cell death, and which have more secondary nature to brain damage acting as aggravating factors.

Animals↗

PubMed2007

Pyruvate modifies glycolytic and oxidative metabolism of rat embryonic spinal cord astrocyte cell lines and prevents their spontaneous transformation.

This study aimed to provide detailed data on mitochondrial respiration of normal astrocyte cell lines derived from rat embryonic spinal cord. Astrocytes in early passages (EP), cultured without pyruvate for more than 35 passages, defined here as late passages (LP), undergo spontaneous transformation. To study initial steps in cell transformation, EP data were compared with those of LP cells. LP cells had reduced glycolysis, fewer mitochondria and extremely low oxidative rates, resulting from a dysfunction of complexes I and II + III of the respiratory chain. Treatment of EP cells with pyruvate until they were, by definition, LP cultures prevented transformation of these cells. Pyruvate-treated EP cells had more mitochondria than normal cells but slightly lower respiratory rates. The increase of mitochondrial content thus appears to act as a compensatory effect to maintain oxidative phosphorylation in these LP 'non-transformed' cells, in which mitochondrial function is reduced. However, pyruvate treatment of transformed LP cells during additional passages did not significantly restore their oxidative metabolism. These data highlight changes accompanying spontaneous astrocyte transformation and suggest potential targets for the control of astrocyte proliferation and reaction to various insults to the central nervous system.

Aging↗

PubMedDate not supplied

Fatty acid beta-oxidation-dependent bioactivation of halogenated thiaalkanoic acids in isolated rat hepatocytes.

5,6-Dichloro-4-thia-5-hexenoic acid (DCTH), the desamino analog of the nephrotoxic cysteine S-conjugate S-(1,2-dichlorovinyl)-L-cysteine, is toxic to liver and kidney mitochondria. The mechanism by which DCTH produces mitochondrial dysfunction has not been defined. The objective of the present experiments was to test the hypothesis that DCTH is bioactivated by the mitochondrial fatty acid beta-oxidation system to cytotoxic intermediates. Incubation of isolated rat hepatocytes with DCTH produced a time- and concentration-dependent decrease in cell viability. The even-chain, elongated analog 7,8-dichloro-6-thia-7-octenoic acid was also cytotoxic, whereas the odd-chain-length analogs 6,7-dichloro-5-thia-6-heptenoic acid and 8,9-dichloro-7-thia-8-nonenoic acid were not. Sodium benzoate reduced the cytotoxicity of DCTH, indicating a role for coenzyme A in the bioactivation of DCTH. DCTH decreased cellular ATP concentrations, the cellular energy charge, and cellular glutathione concentrations; these changes preceded the decrease in cell viability, indicating that mitochondrial dysfunction may be an early event in DCTH-induced cytotoxicity. 6-Chloro-5,5,6-trifluoro-4-thiahexanoic acid and 5,6,7,8,8-pentachloro-4-thia-5,7-octadienoic acid were also cytotoxic in isolated hepatocytes, whereas 4-(2-benzothiazolyl)-4-thiabutanoic acid was not. These data are consistent with the hypothesis that the mitochondrial fatty acid beta-oxidation system is involved in the bioactivation of DCTH and that mitochondria may be important cellular targets in DCTH-induced cytotoxicity.

Animals↗

PubMed1996

Sequence of alterations in subcellular organelles during the development of heart dysfunction in diabetes.

Although changes in different subcellular organelles such as myofibrils, sarcoplasmic reticulum (SR), mitochondria and sarcolemma (SL), as well as in heart function have been reported to occur in chronic diabetes, their inter-relationships and functional significance are poorly understood. In order to gain information on this aspect, diabetes in rats was induced by an intravenous injection of streptozotocin and animals were assessed hemodynamically at 15-27 days. Ventricular tissue from several diabetic animals was pooled, subcellular organelles were isolated and their biochemical activities determined. Significant depressions in cardiac contractile and relaxation were observed to be associated with decreases in myofibrillar Ca(2+)-stimulated ATPase and SR Ca(2+)-pump activities at 21 days from the induction of diabetes. Likewise, the SL Na+-Ca2+ exchange and Ca(2+)-channel density were decreased at 21 days but the affinity of SL Ca(2+)-channels was increased in the diabetic heart. The SL Ca(2+)-pump and Na+-K+ ATPase activities were depressed at 18 and 24 days, respectively. Both alpha- and beta- adrenoceptor densities in SL were decreased at 27 days whereas no changes in mitochondrial function were observed at these early stages of diabetes. The SL low affinity Ca(2+)-binding was decreased while the low affinity Ca(2+)-ATPase activity was increased at 18 days following the induction of diabetes. These results indicate that SL defects precede those in SR, myofibrils or mitochondria and suggest that abnormalities in Ca(2+)-handling as well as interaction of Ca2+ with myofilaments in cardiomyocytes may lead to the development of heart dysfunction in chronic diabetes.

Adenosine Triphosphatases↗

PubMedDate not supplied

Role of heat shock protein 60 (HSP60) on paraquat intoxication.

The possibility of establishing a new method of treatment against pulmonary fibrosis caused by acute paraquat intoxication, which takes into consideration the role of heat shock protein 60 (HSP60), was investigated in paraquat-exposed rat lung mitochondria. In polyacrylamide electrophoresis, mitochondrial protein bands appeared, especially in the range of molecular weight 60 kDa and higher, whereas protein bands disappeared in the 20-40 kDa range on the 4th day after paraquat exposure. The protein profile was normalized on the 7th day and no remarkable changes were seen thereafter up to the 56th day. The changes seen during the observation period were thought to reflect the course of paraquat-induced dysfunction and subsequent repair. The malondialdehyde concentration in mitochondria decreased until the 7th day but subsequently increased and recovered to normal levels by the 56th day. The relative density of HSP60 increased until the 7th day but subsequently decreased and recovered to normal levels by the 56th day. These two parameters therefore showed symmetrical changes. The change in the malondialdehyde concentration was thought to reflect the course of activation of the antioxidation function in mitochondria and the progression of repair. The change in the relative density of HSP60 was thought to have increased to repair the proteins affected by the paraquat radical and to have normalized with the progression of healing. These results suggest that HSP60 may play an important role in preventing the progression of pulmonary fibrosis induced by paraquat.

Animals↗

PubMed1998

Mitochondrial transfer between oocytes: potential applications of mitochondrial donation and the issue of heteroplasmy.

The developmental competence of mouse and human early embryos appears to be directly related to the metabolic capacity of a finite complement of maternally inherited mitochondria that appear to begin to replicate after implantation. Mitochondrial dysfunctions resulting from a variety of intrinsic and extrinsic influences, including genetic abnormalities, hypoxia and oxidative stress, can profoundly influence the level of ATP generation in oocytes and early embryos, which in turn may result in aberrant chromosomal segregation or developmental arrest. Deletions and mutations in oocyte mitochondrial DNA may subtend metabolic deficiencies or replication disorders in some infertile women and in women of increased reproductive age. Here, we describe methods for (i) the compartmentalization of mouse and human oocyte mitochondria into unique cytoplasts enriched for these organelles, and (ii) their transfer by microinjection into intact recipient oocytes. Metabolically active mitochondria in donor and recipient metaphase II stage oocytes were labelled with mitochondria-specific fluorescent probes, and the fate and location of donated mitochondria in recipient oocytes were followed by conventional epifluorescence and scanning laser confocal fluorescence microscopy. The net ATP content of undisturbed and recipient oocytes from the same cohort(s) was measured quantitatively at timed intervals after mitochondrial injection. The results demonstrate the feasibility of isolating and transferring mitochondria between oocytes, an apparent increase in net ATP production in the recipients, and the persistence of activity in the transferred mitochondria. The findings are discussed with respect to mitochondrial function and dysfunction in mammalian oocytes and embryos, and to the potential clinical applications of mitochondrial donation as they relate to the creation of heteroplasmic embryos.

Adenosine Triphosphate↗

PubMed1994

An evaluation of the measurement of the activities of complexes I-IV in the respiratory chain of human skeletal muscle mitochondria.

The measurement of individual respiratory chain complexes is an important component of the investigation of diseases due to mitochondrial dysfunction. We have evaluated assays which measure complexes I to IV in human skeletal muscle mitochondria and in addition optimized these assays to provide sensitive and reliable diagnostic techniques, particularly in situations where a partial interruption at a single complex needs to identified. Using several established methods of membrane disruption we have found that optimal activities of complexes I and II are obtained by freeze-thawing the mitochondria in hypotonic potassium phosphate buffer, whereas complex III and IV activities are markedly increased by the addition of the detergent n-dodecyl-beta-D-maltoside. Complex I activity is measured in the presence of 2.5 mg.ml-1 bovine serum albumin, which increases rotenone sensitivity, and we have shown that NADH-cytochrome b5 reductase makes an important contribution to the rotenone-insensitive NADH-ubiquinone oxidoreductase activity. Complex II activity is measured after preincubation of the mitochondrial fraction with succinate to fully activate the complex. Complex I and III activities are dependent upon the length of the isoprenoid chain of the ubiquinone and ubiquinol, respectively. These assays have been used to establish a control range.

Cytochromes b5↗

PubMed2001

Mitochondrial involvement in antiretroviral therapy-related lipodystrophy.

OBJECTIVES: The management of HIV infection has greatly improved during recent years essentially because of the appearance of new antiretroviral drugs. Highly active antiretroviral therapy (HAART) has achieved important reductions of viraemia and significant recoveries of CD4(+) cell counts in HIV-infected patients. Nonetheless, cases of HIV-infected individuals experiencing lipodystrophy (LD) are being increasingly reported. The purpose of this work was to analyse whether the presence of mitochondrial abnormalities is a frequent feature in LD, since we previously detected mitochondrial abnormalities in an HIV-patient. The second main objective was to study whether LD could be associated with a specific drug. DESIGN: Seven HIV patients presenting LD and five HIV non-LD controls participated in the study. LD patients met the following criteria: (1) LD was their only clinical abnormality, (2) LD was clinically relevant, (3) compliance with antiretroviral treatment was higher than 90% and (4) patients did not have personal or familial history suggestive of mitochondrial disease or neuromuscular disorder. METHODS: Histological stainings, histo-enzymatic reactions, enzymatic and respiratory activities of mitochondrial respiratory chain complexes, and mitochondrial DNA (mtDNA) depletion and rearrangements were examined on muscle mitochondria. RESULTS: Structural muscle abnormalities, mitochondrial respiratory chain dysfunction or mtDNA deletions were detected in all HIV lipodystrophic patients. CONCLUSIONS: The mitochondrial abnormalities found suggest that mitochondrial dysfunction could play a role in the development of antiretroviral therapy-related lipodystrophy.

Adult↗

PubMed2006

Citrobacter rodentium infection causes both mitochondrial dysfunction and intestinal epithelial barrier disruption in vivo: role of mitochondrial associated protein (Map).

Enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli are non-invasive attaching/effacing (A/E) bacterial pathogens that infect their host's intestinal epithelium, causing severe diarrhoeal disease. These bacteria utilize a type III secretion apparatus to deliver effector molecules into host cells, subverting cellular function. Mitochondrial associated protein (Map) is a multifunctional effector protein that targets host cell mitochondria and contributes to infection-induced epithelial barrier dysfunction in vitro. Unfortunately, the relevance of these actions to the pathogenesis of EPEC-induced disease is uncertain. Using Citrobacter rodentium, a mouse-adapted A/E bacterium, we found that Map colocalized with host cell mitochondria, and that in vivo infection led to a disruption of mitochondrial morphology in infected colonocytes as assessed by electron microscopy. Histochemical staining for the mitochondrial enzyme succinate dehydrogenase also revealed a significant loss of mitochondrial respiratory function in the infected intestinal epithelium; however, both pathologies were attenuated in mice infected with a Deltamap strain. C. rodentium Map was also implicated in the disruption of epithelial barrier function both in vitro and in vivo. These studies thus advance our understanding of how A/E pathogens subvert host cell functions and cause disease, demonstrating that Map contributes to the functional disruption of the intestinal epithelium during enteric infection by C. rodentium.

Animals↗

PubMed2004

Hyperglycemia does not alter state 3 respiration in cardiac mitochondria from type-I diabetic rats.

Cardiovascular complications are the primary cause of death for diabetic patients. Clinically, the development of dysfunctional cardiomyopathy is one of the main complications of diabetes. Experimental evidence indicates that the mitochondrion is one of the main sites implicated in the development of cardiac dysfunction. Yet, the precise cause and mechanisms involved in the process are largely debated. We report here that heart mitochondria from streptozotocin-induced diabetic Sprague-Dawley rats present a gradual reduction in state 3 oxygen consumption that reaches 35% by the fourth week following diabetes onset. Rats presenting a level of hyperglycemia similar to diabetic animals, but not showing the marked weight loss or appearance of urinary ketones typical of the later group present no decline in state 3 mitochondrial oxygen consumption, the values being indistinguishable from those of mitochondria from control animals. Mitochondria from hyperglycemic non-ketotic rats, however, show a 15-20% increase in state 4 respiration, but only when glutamate is used as energetic substrate. Mitochondria from diabetic rats, instead, show a 40-50% increase in state 4 respiration with glutamate and 20-25% with succinate as energetic substrate. Interestingly, hyperglycemic non-ketotic animals present a level of serum insulin intermediate between those of controls and diabetic animals. These functional modifications are unrelated to the time elapsed since the onset of diabetes, as they are observed at 2, 4, 6 as well as 8 and 12 weeks after diabetes onset. Taken together, these data argue against hyperglycemia per se being a direct cause of the decline in state 3 oxygen consumption observed in cardiac mitochondria of type-I diabetic rats. Rather, they point to insulin level and subsequent metabolic alterations as a possible cause for the insurgence of mitochondrial dysfunction.

Animals↗

PubMed2005

Aging-related changes of intracellular Ca2+ stores and contractile response of intestinal smooth muscle.

In this study, we investigated the effect of aging on intracellular Ca2+ stores, as sarcoendoplasmic reticulum (SR) and mitochondria, and the influence of these compartments on contraction of rat colon smooth muscle [Bitar, K.N., 2003. Aging and neural control of the GI tract V. Aging and gastrointestinal smooth muscle: from signal transduction to contractile proteins. Am. J. Physiol. Gastrointest. Liver. Physiol. 284(1), G1-G7; Marijic, J., Li, Q.X., Song, M., Nishimaru, K., Stefani, E., Toro, L., 2001. Decreased expression of voltage-and Ca2+-activated K+ channels in coronary smooth muscle during aging. Circ. Res. 88, 210-234; Rubio, C., Moreno, A., Briones, A. Ivorra, M.D., D'Ocon, P., Vila, E., 2002. Alterations by age of calcium handling in rat resistance arteries. J. Cardiovasc. Pharmacol. 40(6), 832-840]. Calcium stores and contraction were evaluated by simultaneous measurements of fluorescence and tension in smooth muscle strips loaded with fura-2. Results showed that activation of muscarinic receptors by methylcholine (MCh, 10 microM), induced a greater contraction in aged rats than in adult animals. The inhibition of Ca2+ ATPase by thapsigargin (TG, 1 microM) did not prevent the refilling of SR either in adult or aged rats. MCh, in the presence of TG, induced an increase in transient fluorescence, indicating a release of Ca2+ from TG-insensitive compartment. The mitochondrial uncoupler, FCCP (5 microM), caused a greater increase in intracellular Ca2+ and tension in aged rats, indicating that mitochondria may accumulate more Ca2+ during aging. The present results show that changes in intracellular Ca2+ stores, such as mitochondria and SR, affect contraction and may cause dysfunctions during aging that could culminate in severe alterations of Ca2+ homeostasis and cell damage.

Aging↗

PubMed2005

Mitochondria as a target for early detection and diagnosis of cancer.

Mitochondrial dysfunction and mutations in mitochondrial DNA (mtDNA) have been frequently reported in cancer, neurodegenerative diseases, diabetes, and aging syndromes. The mitochondrion genome (16.5 Kb) codes only for a small fraction (estimated to be 1%) of the proteins housed within this organelle. The other proteins are encoded by the nuclear DNA (nDNA) and transported into the mitochondria. The identification of mitochondrial proteins that are aberrantly expressed in cancer cells and other diseases is now possible through recent developments in proteomic and bioinformatic technologies. These developments set the stage for a comprehensive organelle-based proteomic approach for the identification of new markers for the early detection, risk assessment, and diagnosis of cancer, and other diseases and for the identification of new targets for therapeutic prevention and intervention.

Animals↗

PubMed2000

Detection of DNA base-excision repair activity for oxidative lesions in adult rat brain mitochondria.

Endogenous oxidative damage to brain mitochondrial DNA and consequential disturbances of gene expression and mitochondrial dysfunction have long been implicated in aging and the pathogenesis of neurodegenerative diseases. It has yet to be determined, however, whether mitochondria in brain cells contain an active DNA repair system and, if so, how this system functions. Therefore, the capacity for the repair of defined types of oxidative DNA lesions has been investigated in adult rat brain mitochondria. Using in vitro DNA incorporation repair assay, we have detected base excision repair (BER) activity for the common oxidative DNA adduct 8-hydroxyl-2'-deoxyguanine (8-oxodG) in mitochondria protein extracts from cortical tissues and cultured primary cortical neurons and astrocytes. The levels of BER activity were both protein concentration-dependent and repair-incubation time-dependent. To resolve the BER pathway, the activity of essential BER enzymes was examined in mitochondria using oligonucleotide incision assay, DNA polymerase assay, and DNA ligase assay employing specific DNA substrates. Mitochondrial extracts were able to remove specifically 8-oxodG, uracil, and the apurinic/apyrimidinic abasic site from substrates. Moreover, a gamma-like DNA polymerase activity and a DNA ligase activity were detected in mitochondiral extracts, based on the formation of specific repair products. These results demonstrate that adult brain mitochondria possess an active BER system for repairing oxidative DNA lesions. This repair system appears to function by sequential actions of DNA repair enzymes that are homologous to, but not identical to, that in the nucleus. Thus, BER may represent an endogenous protective mechanism against oxidative damage to mitochondrial, as well as nuclear, genomes in brain cells.

Animals↗

PubMed2005

Inter-genomic cross talk between mitochondria and the nucleus plays an important role in tumorigenesis.

Mitochondrial dysfunction is a hallmark of cancer cells. Consistent with this phenotype mutations in mitochondrial genome have been reported in all cancers examined to date. However, it is not clear whether mitochondrial genomic status in human cells affects nuclear genome stability and whether proteins involved in inter-genomic cross talk are involved in tumorigenesis. Using cell culture model and cybrid cell technology, we provide evidence that mitochondrial genetic status impacts nuclear genome stability in human cells. In particular our studies demonstrate 1) that depletion of mitochondrial genome (rho0) leads to chromosomal instability (CIN) reported to be present in variety of human tumors and 2) rho0 cells show transformed phenotype. Our study also demonstrates that mitochondrial genetic status plays a key role in regulation of a multifunctional protein APE1 (also known as Ref1 or HAP1) involved in transcription and DNA repair in the nucleus and the mitochondria. Interestingly we found that altered expression of APE1 in rho0 cells and tumorigenic phenotype can be reversed by exogenous transfer of wild type mitochondria in rho0 cells. Furthermore, we demonstrate that APE1 expression is altered in variety of primary tumors. Taken together, these studies suggest that inter-genomic cross talk between mitochondria and the nucleus plays an important role in tumorigenesis and that APE1 mediates this process.

Blotting, Western↗

PubMed2005

Transient cerebral ischemia induces delayed proapoptotic Bad translocation to mitochondria in CA1 sector of hippocampus.

Delayed ischemic brain damage is associated with mitochondrial dysfunction, but the underlying mechanisms are not known in detail. Recent data suggest that the process is associated with multidirectional changes in the activities of various proteins located in mitochondria. Of these, the stress-activated kinase JNK is delay-activated postischemia. We induced 5 min cerebral ischemia in gerbils followed by 3, 24, 48, 72 and 96 h of reperfusion. Here we show the postischemic translocation of proapoptotic protein Bad to mitochondria. Immunoelectron microscopic examination revealed the co-appearance of Bad and Bcl-2 proteins in postischemic mitochondria in ischemia-vulnerable CA1 sector of hippocampus as opposed to the ischemia-resistant DG region. Mitochondrial increase of Bad protein is coincident with a transient decrease of the active, phosphorylated form of prosurvival kinase, Raf-1, under conditions of long reperfusion. The above demonstrated sequence of events is likely to play a role in delayed postischemic nerve cell death.

Analysis of Variance↗