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PubMed2006

Mitochondrial dysfunction in focal segmental glomerulosclerosis of puromycin aminonucleoside nephrosis.

Focal segmental glomerular sclerosis (FSGS) is a major renal complication of mitochondrial (mt) cytopathies. The present study was designed to investigate the possibility of mtDNA lesion accumulation in podocytes, which are a primary pathogenic site of FSGS, during the development of glomerulopathy in puromycin aminonucleoside nephrosis (PAN). Two renal pathological phases of PAN, nephrosis phase and FSGS phase were studied. We investigated the expression of mt proteins, the copy number of a 4834 base-pair deletion (del-mtDNA), and total mtDNA content by real-time polymerase chain reaction, as well as the mRNA expression levels of the mt transcription factor A (mtTFA) and the nuclear respiratory factor-1 (NRF-1) in glomeruli. The mtDNA encoded cytochrome c oxidase subunit I (COX I) protein level was identical to control in nephrosis phase, however, a 45% reduction was seen in FSGS phase. Intraglomerular del-mtDNA was 16-21 times higher than controls in both phases, but the proportion of this mutation was <1% of total mtDNA. The copy number of total mtDNA at nephrosis phase increased up to 241%, whereas, it decreased to 34% at FSGS phase in glomeruli. The mRNA expression of both mtTFA and NRF-1 was upregulated at nephrosis phase, but mtTFA was downregulated at FSGS phase. A reduction in mtDNA copy number resulted in reduced levels of COX I in glomeruli at FSGS phase, suggesting that mt dysfunction by mtDNA depletion potentially plays a key role in the pathogenesis of FSGS in PAN.

Animals↗

PubMed2005

Reverse transcriptase inhibitors alter uncoupling protein-1 and mitochondrial biogenesis in brown adipocytes.

OBJECTIVE: Human adipose depots contain remnant brown adipocytes interspersed among white adipocytes, and disturbances of brown with respect to white adipocyte biology have been implicated in highly active antiretroviral therapy (HAART)-induced lipomatosis. Brown adipocytes express the uncoupling protein-1 (UCP1) and contain a large number of mitochondria, potential targets of HAART toxicity. The aim of this study was to evaluate the effects of reverse transcriptase inhibitors (RTIs) on primary brown adipocytes differentiated in culture. DESIGN AND METHODS: We analysed the effects of RTIs, nucleoside analogues (NRTIs: stavudine, zidovudine, didanosine and lamivudine) and non-nucleoside analogues (NNRTIs: nevirapine and efavirenz), on differentiation, mitochondrial biogenesis and gene expression in brown adipocytes. RESULTS: None of the NRTIs altered brown adipocyte differentiation whereas NNTRIs had differing effects. Efavirenz blocked lipid deposition and expression of adipose marker genes but nevirapine induced lipid accumulation and adipose gene expression, promoted mitochondrial biogenesis and increased UCP1. Stavudine, zidovudine and didanosine reduced mitochondrial DNA (mtDNA) content. However, mitochondrial genome expression was only impaired in didanosine-treated adipocytes. Stavudine, but not zidovudine, induced expression of the mitochondrial transcription factors and this may explain compensatory mechanisms for the depletion of mtDNA by up-regulating mtDNA transcription. Stavudine caused a specific induction of UCP1 gene expression through direct interaction with a retinoic acid-dependent pathway. CONCLUSIONS: Specific disturbances in brown adipocytes in adipose depots may contribute to HAART-induced lipomatosis. Mitochondrial depletion does not appear to be the only mechanism explaining adverse effects in brown adipocytes because there is evidence of compensatory mechanisms that maintain mtDNA expression, and the expression of the UCP1 gene is specifically altered.

Adipose Tissue, Brown↗

PubMed1997

Nonneutral evolution of tandem repeats in the mitochondrial DNA control region of lagomorphs.

The mitochondrial DNA of the European rabbit (Oryctolagus cuniculus) contains a tandem array of 153-bp repeats in the vicinity of the replication origin of the H-stand. Variation among molecules in the number of these repeats results in inter- and intraindividual length polymorphism (heteroplasmy). Generally, in an individual, one predominant molecular type is observed, the others representing a low percentage of the mtDNA content. At the tissue level, we observe a particular distribution of this polymorphism in the gonads compared with liver, kidneys, or brain, implying a relationship between the differentiation status of the cells and the types of new mtDNA molecules which appear and accumulate during lifetime. Similar tandem repeats were also found in the mtDNA noncoding region of European hares (Lepus europaeus), a cottontail (Sylvilagus floridanus), and a pika (Ochotona rufescens). The lengths and the sequences of these units evolve rapidly and in a concerted way, but the number of repeats is maintained in a narrow range, and an internal 20-bp segment is highly conserved. Constraints restrict the evolution of the primary sequence of these repeated units, the number of which is probably controlled by a stabilizing selection.

Animals↗

PubMed2004

Mitochondrial DNA levels in fat and blood cells from patients with lipodystrophy or peripheral neuropathy and the effect of 90 days of high-dose coenzyme Q treatment: a randomized, double-blind, placebo-controlled pilot study.

BACKGROUND: Mitochondrial toxicity can be induced by reverse-transcriptase inhibitors, and an association between levels of mitochondrial DNA (mtDNA) per cell and lipodystrophy, peripheral neuropathy, and HIV infection per se has been suggested. Studies aimed at increasing the oxidative capacity in HIV-infected patients have been sparse. METHODS: Levels of mtDNA in fat and peripheral blood mononuclear cells (PBMCs) from 25 HIV infected patients and 10 healthy control subjects were studied with real-time PCR analysis. A placebo-controlled and double-blind design was used to assign individuals to receive either 100 mg of coenzyme Q twice daily for 3 months or a matching placebo regimen. Levels of mtDNA and other parameters were assessed before and after the intervention period. RESULTS: The mean number of mtDNA copies per cell was lower in fat tissue obtained from patients with peripheral neuropathy (1547 mtDNA copies/cell; P=.045), patients with lipodystrophy (1732 mtDNA copies/cell; P=.003) and in HIV patients with no complications associated with highly active antiretroviral therapy (2935 mtDNA copies/cell; P=.078), compared with healthy control subjects (6198 mtDNA copies/cell). No clear difference was seen in mtDNA content in PBMCs. Coenzyme Q therapy improved the general condition of patients (P=.005) and caused a reversible increase in peripheral neuropathy pain (P=.048). Compared with placebo, treatment with coenzyme Q did not result in changes in mtDNA levels in fat cells or in PBMCs after the treatment period. CONCLUSIONS: Levels of mtDNA in fat tissue, but not in PBMCs, were associated with peripheral neuropathy and lipodystrophy. High-dose coenzyme Q therapy increased well-being in asymptomatic HIV-infected patients and those with lipodystrophy, as well as in control subjects, but aggravated pain in patients with peripheral neuropathy.

Adipocytes↗

PubMed2005

Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine.

OBJECTIVE: To determine if stavudine (alpha4T)-associated mitochondrial toxicity could be reversed by substitution with another nucleoside reverse transcriptase inhibitor. As apoptosis and dysfunction of electron transport chain (ETC) activities may underlie mitochondrial toxicity, these parameters were also evaluated. DESIGN: The 16 participants (on d4T for >3 years; with lipoatrophy and/or hyperlactatemia) substituted abacavir or zidovudine for stavudine in their antiretroviral regimen. Key parameters including dual-energy X-ray absorptiometry (DEXA) scans, fat apoptosis, mitochondrial DNA (mtDNA) content in peripheral blood mononuclear cells (PBMC), skeletal muscle and fat, as well as skeletal muscle mitochondrial ETC activities were evaluated at study entry and at 48 weeks after the substitution. METHODS: Quantitative PCR was used to evaluate mtDNA levels and the presence of deletions/rearrangements; CLIA-validated methods for ETC activities; terminal deoxynucleotidyl transferase dUTP-digoxigenin nick-end labeling assays to evaluate adipocyte apoptosis; and DEXA scans to measure changes in body fat. RESULTS: MtDNA was depleted at study entry in muscle, adipose tissue and PBMC but levels rebounded with respective mean increases of 141%, 146%, and 369% at week 48. Corresponding fat improvements were noted with DEXA increases of 21%, 11%, and 16% in arm, leg, and trunk, respectively. Quantitative adipocyte apoptosis were significantly increased at baseline (P < 0.01 versus HIV-negative controls), with a significant reduction at week 48 (P < 0.05 versus baseline). Mean values for seven mitochondrial enzyme activities assays at entry indicated substantial loss of function (48% to 85% of controls) with significant improvement of complex I activity by week 48. CONCLUSIONS: Substitution of stavudine with abacavir or zidovudine improves mitochondrial indices and fat apoptosis in the setting of lipoatrophy.

Adipocytes↗

PubMed2004

Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine.

The "D drug" HIV reverse-transcriptase inhibitors zalcitabine, didanosine, and stavudine are relatively strong inhibitors of polymerase-gamma compared with the "non-D drugs" zidovudine, lamivudine, and abacavir. D drugs deplete mitochondrial DNA (mtDNA) in cultured hepatocytes. This mtDNA depletion is associated with an increased in vitro production of lactate. To investigate the origin of hyperlactatemia in HIV-infected patients and the effects of antiretroviral therapy on liver mtDNA, we biopsied liver tissue from 94 individuals with chronic hepatitis C virus (HCV) infection. Eighty subjects were coinfected with HIV. Serum lactate was measured at the time of biopsy. Hepatic mtDNA and liver histology were centrally assessed. Liver mtDNA content of HIV-infected patients receiving D drugs at the time of biopsy (n = 34) was decreased by 47% (P<.0001) compared with those without D drugs (n = 35). Aside from a possible association between HCV genotype I status and mtDNA depletion in multivariate analysis, there were no other virologic, immunologic, histologic, demographic or treatment-related variables that could explain the mtDNA depletion. Lactate was above the upper limit of normal in only three patients, all of whom were treated with D drugs. The mtDNA in each of them was lower than in any non-D drug patient and significantly (P =.017) depleted compared with D drug patients with normal lactate. In conclusion, D drug treatment is associated with decreased hepatic mtDNA in HIV-infected patients with chronic HCV infection. Moderate mtDNA depletion in liver does not necessarily lead to hyperlactatemia, but more pronounced decreases in hepatic mtDNA may be an important contributor to lactate elevation.

Acidosis, Lactic↗

PubMed2001

Mitochondrial transcription factor A (mtTFA) and diabetes.

Mitochondrial DNA (mtDNA) content decreased in an age-dependent manner and may be one of the causal factors in age-related type 2 diabetes. Mitochondrial transcription factor A (mtTFA), which provides the replication primer, plays a key role for the regulation of mtDNA replication and its level is proportional to mtDNA. Here, we studied on the regulatory mechanism of mtTFA expression and the factors affecting the transcriptional activity of the mtTFA promoter. The promoter of human mtTFA contains 67 CpG dinucleotides. When the plasmids bearing the mtTFA promoter (2378 bp) linked to luciferase were transiently transfected into HepG2 cells, in vitro methylation of NRF-1 site by HhaI methylase abolished the mtTFA promoter activity up to 90%, implying that the CpG methylation of NRF-1 site inactivate mtTFA promoter-driven transcriptional activity. Besides the promoter methylation, the exogenous hydrogen peroxide or glucose also modulates the promoter activity of mtTFA. The bacterially overexpressed mtTFA protein exhibits a strong binding affinity to circular DNA (perhaps to mtDNA in mitochondria in vivo) and the protection of the DNA from cleavage by a hydrogen peroxide attack. Taken all these results together, age-related alterations of oxidative stress may affect mtDNA replication via regulating mtTFA activity. Furthermore, a vicious cycle may be present between mtTFA protein level and oxidative stress in the sense of DNA damage. Further studies were necessary to prove the presence of methyl cytosine in the mtTFA promoter of either an aged or a diabetic person and the effect of oxidative stress on the mtTFA function and expression resulting in a change of the mtDNA copy number.

Amino Acid Sequence↗

PubMed2003

Comparative effects of adefovir and selected nucleoside inhibitors of hepatitis B virus DNA polymerase on mitochondrial DNA in liver and skeletal muscle cells.

Adefovir is a potent nucleotide analog inhibitor of hepatitis B virus (HBV) DNA polymerase. Its oral prodrug adefovir dipivoxil has been approved for the treatment of chronic HBV infection. In this study, adefovir was characterized for its in vitro effects on mitochondrial DNA (mtDNA) synthesis and compared with the nucleoside analogues lamivudine (3TC), fialuridine (FIAU), and zalcitabine (ddC). No substantial changes in mtDNA content were detected in human hepatoblastoma HepG2 cells and normal human skeletal muscle cells following a 9-day treatment with 0.3-30 microm adefovir, concentrations up to 500-fold higher than the peak serum levels in patients treated with adefovir dipivoxil. Similarly, mtDNA was unchanged in both cell types following treatment with 3TC. In contrast, 30-55% and > 90% reductions in mtDNA were observed following incubation with 30 microm FIAU and ddC, respectively. The effects of FIAU on mtDNA became more pronounced following prolonged 18-day treatment of skeletal muscle cells while the effects of other drugs remained unchanged.

Adenine↗

PubMed1996

Aging-dependent functional alterations of mitochondrial DNA (mtDNA) from human fibroblasts transferred into mtDNA-less cells.

To investigate the role that aging-dependent accumulation of mitochondrial DNA (mtDNA) mutations plays in the senescence processes, mitochondria from fibroblasts of 21 normal human individuals between 20 weeks (fetal) and 103 years of age were introduced into human mtDNA-less (rhoo) 206 cells by cytoplast x rhoo cell fusion, and 7-31 transformant clones were isolated from each fusion. A slight cell donor age-dependent decrease in growth rate was detected in the transformants. Using an O2 consumption rate of 1 fmol/min/cell, which was not observed in any transformant among 158 derived from individuals 20 weeks (fetal) to 37 years of age, as a cut-off to identify respiratory-deficient clones, 11 such clones were found among 198 transformants derived from individuals 39-103 years of age. Furthermore, conventional and nonparametric analysis of the respiratory rates of 356 clones revealed a very significant decrease with donor age. In other analyses, a very significant age-dependent decline in the mtDNA content of the clones was observed, without, however, any significant correlation with the decrease in O2 consumption rate in the defective transformants. These observations clearly indicate the occurrence in the fibroblast-derived transformants of two independent, age-related functional alterations of mtDNA, presumably resulting from structural damage to this genome.

Adolescent↗

PubMed1980

Development of the mitochondrial mass and accumulation of mtDNA in previtellogenic stages of Xenopus laevis oocytes.

The development of the mitochondrial mass of the previtellogenic oocytes of Xenopus laevis has been analysed by a morphometric method and it has been correlated with the growth of the occyte itself. The study which was performed with oocytes from females of very different ages shows that the relative size of the mitochondrial mass in the smallest oocytes decreases gradually with the age of the females. Cytophotometric analysis of the Feulgen-stained mitochondrial mass enabled the mtDNA content of that structure to be quantified during its development. This development involves about 12 rounds of replication out of the total 16--17 rounds of replication during complete differentiation of large oocytes. It is possible to estimate the mean replication rate of the mtDNA during the course of the previtellogenic period. The calculated rate of replication is very high in the mitochondrial mass of all the growing oocytes of very young females(about 1--2 months old), then it decreases rapidly when the oocytes reach 120 microns in diameter. These results suggest that the mitochondrial masses found in small oocytes of old females do not correspond to sites of active mitochondrial biogenesis but rather they represent a physiologically arrested collection of organelles. Thus the aggregation of mitochondria is the cytological expression of rapid and strictly localized mitochondriogenesis only in very young females.

Aging↗

PubMed1997

Qualitative and quantitative changes in skeletal muscle mtDNA and expression of mitochondrial-encoded genes in the human aging process.

It has been widely postulated that age-dependent changes in the mitochondrial genetic system may contribute to the human aging process. We recently reported unchanged specific activities of mitochondrial respiratory chain enzymes and a decrease in oxidation capacity of different substrates with aging, due, in part, to some confounding variables such as physical activity or tobacco consumption. The present study deals with age-related changes in muscle mtDNA structure and its biogenesis in humans. We found a low prevalence of mtDNA rearrangements with aging, only detected by PCR. The mtDNA content increased significantly with age (b = 0.0115, P < 0.0001). Also, an unchanged steady-state level of mitochondrial transcripts, a reduced transcription rate (P < 0.0001), and an increase in mitochondrial membrane lipid peroxidation (P < 0.0001) were observed in aging. These data demonstrate that minor structural mtDNA changes appear during the human aging process. By contrast, alterations in mitochondrial homeostasis ultimately producing modifications in mitochondrial biogenesis rates could play a role in the process of human senescence.

Adult↗

PubMedDate not supplied

Age-associated damage in mitochondrial function in rat hearts.

The aim of this study is to elucidate effects of aging on mitochondrial function and mitochondrial DNA (mtDNA) in rat heart and liver. The activities of complex I and complex IV of heart mitochondria of rats aged 100 weeks decreased significantly by 31% and 22%, respectively, compared with those of rats aged 7 weeks. No significant changes were observed in these two parameters in rats aged 7 weeks and aged 55 weeks. There were no significant differences in the specific activities of complex II and complex III among the age groups of 7, 55, and 100 weeks. The mtDNA content decreased by 58% in rats aged 100 weeks compared with that in rats aged 7 weeks. Content of 8-hydroxydeoxyguanosine (8-OH-dG), an oxidative product of deoxyguanosine (dG), increased by 130% in rats aged 100 weeks compared with that in rats aged 7 weeks. No significant changes were observed in these parameters between rats aged 7 weeks and 55 weeks. In contrast to heart mtDNA, these age-dependent changes were not observed in liver mitochondria at rats aged up to 100 weeks. From our results, age-associated decline in mitochondrial function might play an important role in cell aging, particularly in postmitotic cells such as heart muscle, and accumulation of oxidative damage to mtDNA might be involved in this mechanism.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2000

Mitochondrial DNA damage as a mechanism of cell loss in Alzheimer's disease.

Aging is associated with impaired mitochondrial function caused by accumulation of oxygen free radical-induced mitochondrial (Mt) DNA mutations. One prevailing theory is that age-associated diseases, including Alzheimer's disease (AD), may be precipitated, propagated, or caused by impaired mitochondrial function. To investigate the role of MtDNA relative to genomic (Gn) DNA damage in AD, temporal lobe samples from postmortem AD (n = 37) and control (n = 25) brains were analyzed for MtDNA and GnDNA fragmentation, mitochondrial protein and cytochrome oxidase expression, MitoTracker Green fluorescence (to assess mitochondrial mass/abundance), and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG) immunoreactivity. Brains with AD had more extensive nicking and fragmentation of both MtDNA and GnDNA as demonstrated by agarose gel electrophoresis, end-labeling, and the in situ terminal deoxynucleotide transferase end-labeling (TUNEL) assay, and only the brains with AD had detectable 8-OHdG immunoreactivity in cortical neurons. Increased MtDNA damage in AD was associated with reduced MtDNA content, as demonstrated by semiquantitative PCR analysis and reduced levels of Mt protein and cytochrome oxidase expression by Western blot analysis or immunohistochemical staining with image analysis. The finding of reduced MitoTracker Green fluorescence in AD brains provided additional evidence that reduced Mt mass/abundance occurs with AD neurodegeneration. The presence of increased MtDNA and GnDNA damage in AD suggest dual cell death cascades in AD. Impaired mitochondrial function caused by MtDNA damage may render brain cells in AD more susceptible to oxidative injury and thereby provide a mechanism by which systemic or environmental factors could influence the course of disease.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1996

Increase of mtDNA-binding proteins and mitochondrial mRNAs in regenerating liver.

In order to elucidate the mechanism of energy supply for liver regeneration after partial hepatectomy, we investigated mtDNA replication and transcription in regenerating rat liver. Changes of mtDNA-binding proteins, mtDNA, and mitochondrial mRNAs were monitored at 0, 12, 24, 48, 96, and 168 hr after the operation by gel mobility shift assay and Southern and Northern blot analyses, respectively. We focused on mtDNA-binding proteins specific for four different sequence elements possibly involved in regulation of mtDNA replication and transcription. Amounts of all the proteins sharply increased to maximum (4- to 10-fold of the preoperative level) 12 hr after partial hepatectomy and then decreased for 24 hr. After 24 hr, the amount of the respective binding protein changed diversely. Mitochondrial mRNA levels per gram tissue weight were unchanged during the first 12 hr after partial hepatectomy, but dramatically increased to maximum (4-fold) at 24 hr. In contrast, mtDNA content, expressed as a ratio of the nuclear cytochrome c1 gene, was unchanged during the first 48 hr and then started to increase, reaching maximum (1.5-fold) at 4 days. These results suggest that the energy supply in the early stage of the liver regeneration following hepatectomy is achieved mainly through enhancement of mtDNA transcription in which the mtDNA-binding proteins probably play regulatory roles.

Animals↗

PubMed1994

Platelet-mediated transformation of mtDNA-less human cells: analysis of phenotypic variability among clones from normal individuals--and complementation behavior of the tRNALys mutation causing myoclonic epilepsy and ragged red fibers.

In the present work, we demonstrate the possibility of using human blood platelets as mitochondrial donors for the repopulation of mtDNA-less (rho 0) cells. The noninvasive nature of platelet isolation, combined with the prolonged viability of platelet mitochondria and the simplicity and efficiency of the mitochondria-transfer procedure, has substantially increased the applicability of the rho 0 cell transformation approach for mitochondrial genetic analysis and for the study of mtDNA-linked diseases. This approach has been applied to platelets from several normal human individuals and one individual affected by the myoclonic-epilepsy-and-ragged-red-fibers (MERRF) encephalomyopathy. A certain variability in respiratory capacity was observed among the platelet-derived rho 0 cell transformants from a given normal subject, and it was shown to be unrelated to their mtDNA content. The results of sequential transfer of mitochondria from selected transformants into a rho 0 cell line different from the first rho 0 acceptor strongly suggest that this variability reflected, at least in part, differences in nuclear gene content and/or activity among the original recipient cells. A much greater variability in respiratory capacity was observed among the transformants derived from the MERRF patient and was found to be related to the presence and amount of the mitochondrial tRNALys mutation associated with the MERRF syndrome. An analysis of the relationship between proportion of mtDNA carrying the MERRF mutation and degree of respiratory activity in various transformants derived from the MERRF patient revealed an unusual complementation behavior of the tRNALys mutation, possibly reflecting the distribution of mutant mtDNA among the platelet mitochondria.

Adult↗

PubMed1999

Skeletal muscle mitochondrial DNA injury in patients with unilateral peripheral arterial disease.

BACKGROUND: Patients with peripheral arterial disease (PAD) have exercise limitation due to claudication-limited pain and metabolic alterations in skeletal muscle. PAD is also associated with oxidative stress, which is a known cause of mitochondrial DNA (mtDNA) injury. The present study was designed to test the hypothesis that PAD is associated with mtDNA injury, as reflected by an increased frequency of a specific 4977-base pair (bp) mtDNA deletion mutation. METHODS AND RESULTS: The deletion frequency was quantified in gastrocnemius muscle of 8 patients with unilateral PAD and 10 age-matched control subjects with the use of polymerase chain reaction methodologies. Muscle from the hemodynamically unaffected (less affected) PAD limb showed an 8-fold increased deletion frequency and the hemodynamically affected (worse affected) PAD limb had a 17-fold increased deletion frequency compared with muscle from control subjects. The frequency of the 4977-bp deletion in the worse-affected limb was positively correlated with the age of the patients but not the claudication-limited exercise performance of the patients. Total mtDNA content, citrate synthase activity, and cytochrome c oxidase activity were not different in the muscle from the 3 limb populations. However, the ratio of citrate synthase to cytochrome c oxidase was higher in the worse- versus less-affected limbs of PAD patients. CONCLUSIONS: The present study demonstrates a large increase in the frequency of the mtDNA 4977-bp deletion in patients with PAD but in a distribution not limited to the hemodynamically affected limb.

Aged↗

PubMed1992

Mitochondrial DNA damage by anticancer agents.

Mitochondrial DNA (mtDNA) is susceptible to damage by a number of anticancer agents either directly or indirectly. This damage is of little consequence if only a few of the mtDNA molecules are damaged. However, multiple drug treatments could result in a significant effect on a cell's ability to survive. The differential effect of anticancer agents on either organ specific toxicities or selective tumor kill can be partially accounted for by differential mtDNA content of cells and on the basis of differential protective mechanisms within mitochondria of various organs or tumor tissue. The concept of damage to mitochondria, especially its genome, is a subject of active investigation in various laboratories. This area of research may provide mechanism(s) by which organ specific toxicities or tumor specific toxicities may be elaborated. Also, the concept of targeting tumor specific mitochondria and/or mtDNA by anticancer agents is very attractive but has not come to fruition due to a lack of understanding of the regulation of the genome in tumor cells. Future investigations in this arena will enhance our knowledge on the interaction between anticancer agents and extranuclear DNA.

Animals↗

PubMed2006

A novel mutation in the mitochondrial tRNA(Ser(AGY)) gene associated with mitochondrial myopathy, encephalopathy, and complex I deficiency.

PURPOSE: To identify molecular defects in a girl with clinical features of MELAS (mitochondrial encephalomyopathy and lactic acidosis) and MERRF (ragged-red fibres) syndromes. METHODS: The enzyme complex activities of the mitochondrial respiratory chain were assayed. Temporal temperature gradient gel electrophoresis was used to scan the entire mitochondrial genome for unknown mitochondrial DNA (mtDNA) alterations, which were then identified by direct DNA sequencing. RESULTS: A novel heteroplasmic mtDNA mutation, G12207A, in the tRNA(Ser(AGY)) gene was identified in the patient who had a history of developmental delay, feeding difficulty, lesions within her basal ganglia, cerebral atrophy, proximal muscle weakness, increased blood lactate, liver dysfunction, and fatty infiltration of her muscle. Muscle biopsy revealed ragged red fibres and pleomorphic mitochondria. Study of skeletal muscle mitochondria revealed complex I deficiency associated with mitochondrial proliferation. Real time quantitative PCR analysis showed elevated mtDNA content, 2.5 times higher than normal. The tRNA(Ser(AGY)) mutation was found in heteroplasmic state (92%) in the patient's skeletal muscle. It was not present in her unaffected mother's blood or in 200 healthy controls. This mutation occurs at the first nucleotide of the 5' end of tRNA, which is involved in the formation of the stem region of the amino acid acceptor arm. Mutation at this position may affect processing of the precursor RNA, the stability and amino acid charging efficiency of the tRNA, and overall efficiency of protein translation. CONCLUSION: This case underscores the importance of comprehensive mutational analysis of the entire mitochondrial genome when a mtDNA defect is strongly suggested.

Base Sequence↗