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PubMed2000

Mitochondrial oxidative stress in mice lacking the glutathione peroxidase-1 gene.

Oxidative stress resulting from mitochondrially derived reactive oxygen species (ROS) has been hypothesized to damage mitochondrial oxidative phosphorylation (OXPHOS) and to be a factor in aging and degenerative disease. If this hypothesis is correct, then genetically inactivating potential mitochondrial antioxidant enzymes such as glutathione peroxidase-1 (Gpx1; EC 1.11.1.9) should increase mitochondrial ROS production and decrease OXPHOS function. To determine the expression pattern of Gpx1, isoform-specific antibodies were generated and mutant mice were prepared in which the Gpx1 protein was substituted for by beta-galactosidase, driven by the Gpx1 promoter. These experiments revealed that Gpx1 is highly expressed in both the mitochondria and the cytosol of the liver and kidney, but poorly expressed in heart and muscle. To determine the physiological importance of Gpx1, mice lacking Gpx1 were generated by targeted mutagenesis in mouse ES cells. Homozygous mutant Gpx1(tm1Mgr) mice have 20% less body weight than normal animals and increased levels of lipid peroxides in the liver. Moreover, the liver mitochondria were found to release markedly increased hydrogen peroxide, a Gpx1 substrate, and have decreased mitochondrial respiratory control ratio and power output index. Hence, genetic inactivation of Gpx1 resulted in growth retardation, presumably due in part to reduced mitochondrial energy production as a product of increased oxidative stress.

Animals↗
PubMed2001

Hypersensitization of tumor cells to glycolytic inhibitors.

The slow growth of cells in the inner core of solid tumors presents a form of multidrug resistance to most of the standard chemotherapeutic agents, which target the outer more rapidly dividing cells. However, the anaerobic environment of the more centrally located tumor cells also provides an opportunity to exploit their dependence on glycolysis for therapeutic gain. We have developed two in vitro models to investigate this possibility. Model A represents osteosarcoma wild-type (wt) cells treated with agents which inhibit mitochondrial oxidative phosphorylation (Oxphos) by interacting with complexes I, III, and V of the electron transport chain in different ways, i.e., rhodamine 123 (Rho 123), rotenone, antimycin A, and oligomycin. All of these agents were found to hypersensitize wt cells to the glycolytic inhibitor 2-deoxyglucose. Cells treated with Rho 123 also become hypersensitive to oxamate, an analogue of pyruvate, which blocks the step of glycolysis that converts pyruvate to lactic acid. Model B is rho(0) cells which have lost their mitochondrial DNA and therefore cannot undergo Oxphos. These cells are 10 and 4.9 times more sensitive to 2-deoxyglucose and oxamate, respectively, than wt cells. Lactic acid levels, which are a measure of anaerobic metabolism, were found to be > 3 times higher in rho(0) than in wt cells. Moreover, when wt cells were treated with Rho 123, lactic acid amounts increased as a function of increasing Rho 123 doses. Under similar Rho 123 treatment, rho(0) cells did not increase their lactic acid levels. These data confirm that cell models A and B are similarly sensitive to glycolytic inhibitors due to their dependence on anaerobic metabolism. Overall, our in vitro results suggest that glycolytic inhibitors could be used to specifically target the slow-growing cells of a tumor and thereby increase the efficacy of current chemotherapeutic and irradiation protocols designed to kill rapidly dividing cells. Moreover, glycolytic inhibitors could be particularly useful in combination with anti-angiogenic agents, which, a priori, should make tumors more anaerobic.

Anaerobiosis↗
PubMed1997

Genes of human ATP synthase: their roles in physiology and aging.

The reaction of ATP synthase (F0F1) is the final step in oxidative phosphorylation (OXPHOS). Although OXPHOS has been studied extensively in bacteria, no tissue-specific functions nor bioenergetic disease, such as mitochondrial encephalomyopathy and aging occur in these organisms. Recent developments of the Human Genome Project will become an important factor in the study of mammalian bioenergetics. To elucidate the physiological roles of human F0F1, genes encoding the subunits of F0F1 were sequenced, and their expression in human cells was analyzed. The following results were obtained: A. The roles of the residues in F0F1 are not only to transform the energy of the electrochemical potential (delta mu H+) across the membrane, but also to respond rapidly to the changes in the energy demand by regulating the intramolecular rotation of F0F1 with the delta mu H+ and the inhibitors of the ATPase. B. The roles of the control regions of the F0F1 genes, are to coordinate both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) depending on the energy demand of the cells, especially in muscle, C. The cause of the age-dependent decline of ATP synthesis has been attributed to the accumulation of mutations in mtDNA. However, the involvement of nDNA in the decline is also important because of telomere shortening in somatic cells, and age-dependent mtDNA expression analyzed with rho degree cells (cells without mtDNA).

Aging↗
PubMed2004

Mitochondrial disorders: prevalence, myths and advances.

Disorders of mitochondrial oxidative phosphorylation (OXPHOS) are renowned for their variability in clinical features and genetic causes. This makes it difficult to determine their true prevalence, but recent studies have documented a minimum birth prevalence of 13.1/100000 or 1/7634 for oxidative phosphorylation disorders with onset at any age. This clearly remains an underestimate but it indicates that oxidative phosphorylation disorders can be regarded as the most common group of inborn errors of metabolism. Pathogenic mutations causing human oxidative phosphorylation disorders have now been identified in more than 30 of the 37 mitochondrial DNA genes and in more than 30 nuclear genes. Most of the nuclear gene defects cause autosomal recessive diseases, but autosomal dominant and X-linked disorders also occur. It is likely that at least another 30, and perhaps over 100, nuclear-encoded oxidative phosphorylation disorders await identification. Oxidative phosphorylation genetics are complex and there appear to be a number of common misconceptions about mitochondrial DNA mutations that may impede optimal investigation and management of patients. In our experience, mitochondrial DNA mutations are not a negligible cause of OXPHOS disorders in children but account for 20-25% of cases. Similarly, a family history suggesting maternal inheritance is the exception rather than the norm for children with mitochondrial DNA mutations, many of whom have de novo mutations. Only some mitochondrial DNA mutations disappear from cultured cells, so deficient enzyme activity in fibroblasts does not imply the presence of a nuclear defect. Finally, it is still widely thought that there are very few reproductive options that can be offered to women at risk of transmitting a mitochondrial DNA mutation. While a cautious approach is needed, there is now a consensus that prenatal diagnosis should be offered to some women, particularly those at lower recurrence risk. Preimplantation genetic diagnosis can also be an option.

Humans↗
PubMed2025

Synergistic targeting of cancer cells through simultaneous inhibition of key metabolic enzymes.

As cancer cell specific rewiring of metabolic networks creates potential therapeutic opportunities, we conducted a synthetic lethal screen utilizing inhibitors of metabolic pathways. Simultaneous administration of (R)-GNE-140 and BMS-986205 (Linrodostat) preferentially halted proliferation of ovarian cancer cells, but not of their non-oncogenically transformed progenitor cells. While (R)-GNE-140 inhibits lactate dehydrogenase (LDH)A/B and thus effective glycolysis, BMS-986205, in addition to its known inhibitory activity on Indoleamine 2,3-dioxygenase (IDO1), also restricts oxidative phosphorylation (OXPHOS), as revealed here. BMS-986205, which is being tested in multiple Phase III clinical trials, inhibits the ubiquinone reduction site of respiratory complex I and thus compromises mitochondrial ATP production. The energetic catastrophe caused by simultaneous interference with glycolysis and OXPHOS resulted in either cell death or the induction of senescence in tumor cells, with the latter being eliminated by senolytics. The frequent synergy observed with combined inhibitor treatment was comprehensively confirmed through testing on tumor cell lines from the DepMap panel and on human colorectal cancer organoids. These experiments revealed highly synergistic activity of the compounds in a third of the tested tumor cell lines, correlating with alterations in genes with known roles in metabolic regulation and demonstrating the therapeutic potential of metabolic intervention.

Humans↗
PubMed2005

Mitochondrial DNA and ACTN3 genotypes in Finnish elite endurance and sprint athletes.

Differences in ACTN3 (alpha-actinin 3) genotypes have been reported among endurance and power athletes. Elite athletic performance in endurance sports should also depend on mitochondrial oxidative phosphorylation (OXPHOS) that produces ATP for muscle metabolism. We determined mitochondrial DNA (mtDNA) and ACTN3 genotypes in Finnish elite endurance (n = 52) and sprint (n = 89) athletes, and found that the frequencies of mtDNA haplogroups differed significantly between the two groups. Most notably, none of the endurance athletes belonged to haplogroup K or subhaplogroup J2, both of which have previously been associated with longevity. The frequency of ACTN3 XX genotype was higher and that of RR was lower among Finnish endurance athletes, and, in addition, none of the top Finnish sprinters had the XX genotype. Lack of mtDNA haplogroup K and subhaplogroup J2 among elite endurance athletes suggests that these haplogroups are 'uncoupling genomes'. Such genomes should not be beneficial to endurance-type athletic performance but should be beneficial to longevity, since uncoupling of OXPHOS reduces the production of ATP, reduces the release of reactive oxygen species and generates heat.

Actinin↗
PubMed2004

AIF deficiency compromises oxidative phosphorylation.

Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that, after apoptosis induction, translocates to the nucleus where it participates in apoptotic chromatinolysis. Here, we show that human or mouse cells lacking AIF as a result of homologous recombination or small interfering RNA exhibit high lactate production and enhanced dependency on glycolytic ATP generation, due to severe reduction of respiratory chain complex I activity. Although AIF itself is not a part of complex I, AIF-deficient cells exhibit a reduced content of complex I and of its components, pointing to a role of AIF in the biogenesis and/or maintenance of this polyprotein complex. Harlequin mice with reduced AIF expression due to a retroviral insertion into the AIF gene also manifest a reduced oxidative phosphorylation (OXPHOS) in the retina and in the brain, correlating with reduced expression of complex I subunits, retinal degeneration, and neuronal defects. Altogether, these data point to a role of AIF in OXPHOS and emphasize the dual role of AIF in life and death.

Adenosine Triphosphate↗
PubMed1998

Regulation of mitochondrial biogenesis in brown adipose tissue: nuclear respiratory factor-2/GA-binding protein is responsible for the transcriptional regulation of the gene for the mitochondrial ATP synthase beta subunit.

The regulation of transcription of the gene for the beta subunit of the FoF1 ATP synthase (ATPsynbeta) in brown adipose tissue has been studied as a model to determine the molecular mechanisms for mitochondrial biogenesis associated with brown adipocyte differentiation. The expression of the ATPsynbeta mRNA is induced during the brown adipocyte differentiation that occurs during murine prenatal development or when brown adipocytes differentiate in culture. This induction occurs in parallel with enhanced gene expression for other nuclear and mitochondrially-encoded components of the respiratory chain/oxidative phosphorylation system (OXPHOS). Transient transfection assays indicated that the expression of the ATPsynbeta gene promoter is higher in differentiated HIB-1B brown adipocytes than in non-differentiated HIB-1B cells. A major transcriptional regulatory site was identified between nt -306 and -266 in the ATPsynbeta promoter. This element has a higher enhancer capacity in differentiated brown adipocyte HIB-1B cells than in non-differentiated cells. Electrophoretic shift analysis indicated that Sp1and nuclear respiratory factor-2/GA-binding protein (NRF2/GABP) were the main nuclear proteins present in brown adipose tissue that bind this site. Double-point mutant analysis indicated a major role for the NRF2/GABP site in the enhancer capacity of this element in brown fat cells. It is proposed that NRF2/GABP plays a pivotal role in the co-ordinated enhancement of OXPHOS gene expression associated with mitochondrial biogenesis in brown adipocyte differentiation.

Adipose Tissue, Brown↗
PubMed2001

Mitochondrial polypeptides of the oxidative phosphorylation pathway as potential new targets for anti-cancer therapy.

We have analyzed our own results on upregulated gene expression in human and monkey lymphomas as well as the data published on expression levels of genes in various cancer cells. The analysis suggests an important role of particular subunits of oxidative phosphorylation (OXPHOS) proteins in malignant transformation of the cell. It opens a possibility of designing new anti-cancer drugs aimed at specific inhibition of the expression of definite mitochondrial OXPHOS proteins' subunits including those of NADH-dehydrogenase 4, cytochrome c oxidase 1, and cytochrome b.

Animals↗
PubMed2024

Simultaneous targeting of peripheral and brain tumors with a therapeutic nanoparticle to disrupt metabolic adaptability at both sites.

Brain metastasis of advanced breast cancer often results in deleterious consequences. Metastases to the brain lead to significant challenges in treatment options, as the blood-brain barrier (BBB) prevents conventional therapy. Thus, we hypothesized that creation of a nanoparticle (NP) that distributes to both primary tumor site and across the BBB for secondary brain tumor can be extremely beneficial. Here, we report a simple targeting strategy to attack both the primary breast and secondary brain tumors utilizing a single NP platform. The nature of these mitochondrion-targeted, BBB-penetrating NPs allow for simultaneous targeting and drug delivery to the hyperpolarized mitochondrial membrane of the extracranial primary tumor site in addition to tumors at the brain. By utilizing a combination of such dual anatomical distributing NPs loaded with therapeutics, we demonstrate a proof-of-concept idea to combat the increased metabolic plasticity of brain metastases by lowering two major energy sources, oxidative phosphorylation (OXPHOS) and glycolysis. By utilizing complementary studies and genomic analyses, we demonstrate the utility of a chemotherapeutic prodrug to decrease OXPHOS and glycolysis by pairing with a NP loaded with pyruvate dehydrogenase kinase 1 inhibitor. Decreasing glycolysis aims to combat the metabolic flexibility of both primary and secondary tumors for therapeutic outcome. We also address the in vivo safety parameters by addressing peripheral neuropathy and neurobehavior outcomes. Our results also demonstrate that this combination therapeutic approach utilizes mitochondrial genome targeting strategy to overcome DNA repair-based chemoresistance mechanisms.

Brain Neoplasms↗
PubMed2024

The role of mitochondria in sex- and age-specific gene expression in a species without sex chromosomes.

Mitochondria perform an array of functions, many of which involve interactions with gene products encoded by the nucleus. These mitochondrial functions, particularly those involving energy production, can be expected to differ between sexes and across ages. Here, we measured mitochondrial effects on sex- and age-specific gene expression in parental and reciprocal F1 hybrids between allopatric populations of Tigriopus californicus with over 20% mitochondrial DNA divergence. Because the species lacks sex chromosomes, sex-biased mitochondrial effects are not confounded by the effects of sex chromosomes. Results revealed pervasive sex differences in mitochondrial effects, including effects on energetics and aging involving nuclear interactions throughout the genome. Using single-individual RNA sequencing, sex differences were found to explain more than 80% of the variance in gene expression. Males had higher expression of mitochondrial genes and mitochondrially targeted proteins (MTPs) involved in oxidative phosphorylation (OXPHOS), while females had elevated expression of non-OXPHOS MTPs, indicating strongly sex-dimorphic energy metabolism at the whole organism level. Comparison of reciprocal F1 hybrids allowed insights into the nature of mito-nuclear interactions, showing both mitochondrial effects on nuclear expression, and nuclear effects on mitochondrial expression. While based on a small set of crosses, sex-specific increases in mitochondrial expression with age were associated with longer life. Network analyses identified nuclear components of strong mito-nuclear interactions and found them to be sexually dimorphic. These results highlight the profound impact of mitochondria and mito-nuclear interactions on sex- and age-specific gene expression.

Animals↗
PubMed2003

Oxidative damage to mitochondrial complex I due to peroxynitrite: identification of reactive tyrosines by mass spectrometry.

There is growing evidence that oxidative phosphorylation (OXPHOS) generates reactive oxygen and nitrogen species within mitochondria as unwanted byproducts that can damage OXPHOS enzymes with subsequent enhancement of free radical production. The accumulation of this oxidative damage to mitochondria in brain is thought to lead to neuronal cell death resulting in neurodegeneration. The predominant reactive nitrogen species in mitochondria are nitric oxide and peroxynitrite. Here we show that peroxynitrite reacts with mitochondrial membranes from bovine heart to significantly inhibit the activities of complexes I, II, and V (50-80%) but with less effect upon complex IV and no significant inhibition of complex III. Because inhibition of complex I activity has been a reported feature of Parkinson's disease, we undertook a detailed analysis of peroxynitrite-induced modifications to proteins from an enriched complex I preparation. Immunological and mass spectrometric approaches coupled with two-dimensional PAGE have been used to show that peroxynitrite modification resulting in a 3-nitrotyrosine signature is predominantly associated with the complex I subunits, 49-kDa subunit (NDUFS2), TYKY (NDUFS8), B17.2 (17.2-kDa differentiation associated protein), B15 (NDUFB4), and B14 (NDUFA6). Nitration sites and estimates of modification yields were deduced from MS/MS fragmentograms and extracted ion chromatograms, respectively, for the last three of these subunits as well as for two co-purifying proteins, the beta and the d subunits of the F1F0-ATP synthase. Subunits B15 (NDUFB4) and B14 (NDUFA6) contained the highest degree of nitration. The most reactive site in subunit B14 was Tyr122, while the most reactive region in B15 contained 3 closely spaced tyrosines Tyr46, Tyr50, and Tyr51. In addition, a site of oxidation of tryptophan was detected in subunit B17.2 adding to the number of post-translationally modified tryptophans we have detected in complex I subunits (Taylor, S. W., Fahy, E., Murray, J., Capaldi, R. A., and Ghosh, S. S. (2003) J. Biol. Chem. 278, 19587-19590). These sites of oxidation and nitration may be useful biomarkers for assessing oxidative stress in neurodegenerative disorders.

Amino Acid Sequence↗
PubMed2000

Human mtDNA haplogroups associated with high or reduced spermatozoa motility.

A variety of mtDNA mutations responsible for human diseases have been associated with molecular defects in the OXPHOS system. It has been proposed that mtDNA genetic alterations can also be responsible for sperm dysfunction. In addition, it was suggested that if sperm dysfunction is the main phenotypic consequence, these mutations could be fixed as stable mtDNA variants, because mtDNA is maternally inherited. To test this possibility, we have performed an extensive analysis of the distribution of mtDNA haplogroups in white men having fertility problems. We have found that asthenozoospermia, but not oligozoospermia, is associated with mtDNA haplogroups in whites. Thus, haplogroups H and T are significantly more abundant in nonasthenozoospermic and asthenozoospermic populations, respectively, and show significant differences in their OXPHOS performance.

Base Sequence↗
PubMed2006

Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome.

The microphthalmia with linear skin defects syndrome (MLS, or MIDAS) is an X-linked dominant male-lethal disorder almost invariably associated with segmental monosomy of the Xp22 region. In two female patients, from two families, with MLS and a normal karyotype, we identified heterozygous de novo point mutations--a missense mutation (p.R217C) and a nonsense mutation (p.R197X)--in the HCCS gene. HCCS encodes the mitochondrial holocytochrome c-type synthase that functions as heme lyase by covalently adding the prosthetic heme group to both apocytochrome c and c(1). We investigated a third family, displaying phenotypic variability, in which the mother and two of her daughters carry an 8.6-kb submicroscopic deletion encompassing part of the HCCS gene. Functional analysis demonstrates that both mutant proteins (R217C and Delta 197-268) were unable to complement a Saccharomyces cerevisiae mutant deficient for the HCCS orthologue Cyc3p, in contrast to wild-type HCCS. Moreover, ectopically expressed HCCS wild-type and the R217C mutant protein are targeted to mitochondria in CHO-K1 cells, whereas the C-terminal-truncated Delta 197-268 mutant failed to be sorted to mitochondria. Cytochrome c, the final product of holocytochrome c-type synthase activity, is implicated in both oxidative phosphorylation (OXPHOS) and apoptosis. We hypothesize that the inability of HCCS-deficient cells to undergo cytochrome c-mediated apoptosis may push cell death toward necrosis that gives rise to severe deterioration of the affected tissues. In summary, we suggest that disturbance of both OXPHOS and the balance between apoptosis and necrosis, as well as the X-inactivation pattern, may contribute to the variable phenotype observed in patients with MLS.

Amino Acid Sequence↗
PubMed2004

Mitochondrial toxicity in fetal Erythrocebus patas monkeys exposed transplacentally to zidovudine plus lamivudine.

This study was designed to investigate fetal mitochondrial toxicity in Erythrocebus patas monkeys exposed in utero to zidovudine (AZT) and lamivudine (3TC), and taken at term. Pregnant patas monkeys were given a daily dose of 40 mg AZT (86% of the human daily dose, based on body weight), for the last 10 weeks (50%) of gestation, and a daily dose of 24 mg 3TC (84% of the human daily dose, based on body weight) for the last 4 weeks of gestation. At term, AZT was found to be incorporated into fetal mitochondrial DNA from skeletal muscle, liver, kidney, and placenta. By transmission electron microscopy (EM) drug-exposed fetal cardiac and skeletal muscle cells showed mitochondrial membrane compromise, mitochondrial proliferation, and damaged sarcomeres, while mitochondria in brain cerebrum and cerebellum were morphologically normal. Substantial depletion of oxidative phosphorylation (OXPHOS) Complex I specific activities was observed in heart (87% reduction in mean, p = 0.02) and skeletal muscle (98% reduction in mean, p = 0.002) from drug-exposed fetuses, compared to unexposed fetuses. In addition Complex IV activity was highly depleted (85% reduction in mean, p = 0.004) in skeletal muscle from the drug-exposed fetuses (p = 0.004). Brain cerebrum and cerebellum showed no statistically significant OXPHOS changes with drug exposure. Mitochondrial DNA quantity was substantially depleted (>50%) in heart, skeletal muscle, cerebellum, and cerebrum from drug-exposed fetuses compared to unexposed controls. Overall, the data indicate that significant mitochondrial damage was observed at birth in monkey fetuses exposed in utero to AZT plus 3TC in a human-equivalent dosing protocol.

Animals↗
PubMed2005

A computational model to define the molecular causes of type 2 diabetes mellitus.

BACKGROUND: Metabolic abnormalities associated with type 2 diabetes mellitus (DM2) are caused in part by inadequate insulin action and resulting changes in gene expression in the skeletal muscle. Two recent, independent studies of human skeletal muscle biopsies from ethnically diverse DM2 patients have identified coordinated reductions in the expression of the oxidative phosphorylation (OXPHOS) genes. Whether these reductions are a consequence or a cause of impaired insulin sensitivity remains an open question. METHODS: To address this question and to define the underlying molecular causes consistent with the expression changes reported in the muscle studies, we created a large-scale computable model to analyze the molecular actions and effects of insulin on muscle gene expression. The model enables computer-aided reasoning using over 210,000 molecular relationships assembled from the DM2 literature. RESULTS: We integrated the data from these muscle biopsy studies into the model and used computer-aided causal reasoning to discover mechanisms that can link alterations in OXPHOS genes to decreases in glucose transport, insulin signaling, and risk factors associated to post-transplant diabetes mellitus. CONCLUSIONS: The emerging hypotheses describe biologic effects in DM2 and offer important cues for molecular targeted therapy.

Algorithms↗
PubMed2004

A new role for the von Hippel-Lindau tumor suppressor protein: stimulation of mitochondrial oxidative phosphorylation complex biogenesis.

Although mitochondrial deficiency in cancer has been described by Warburg, many years ago, the mechanisms underlying this impairment remain essentially unknown. Many types of cancer cells are concerned and, in particular, clear cell renal carcinoma (CCRC). In this cancer, the tumor suppressor gene, VHL (von Hippel-Lindau factor) is invalidated. Previous studies have shown that the transfection of the VHL gene in VHL-deficient cells originating from CCRCs could suppress their ability to form tumors when they were injected into nude mice. However, various additional genetic alterations are observed in such cancer cells. In order to investigate whether VHL invalidation was related to the mitochondrial impairment, we have studied the effects of wild-type VHL transfection into VHL-deficient 786-0 or RCC10 cells on their oxidative phosphorylation (OXPHOS) subunit contents and functions. We show that the presence of wild-type VHL protein (pVHL) increased mitochondrial DNA and respiratory chain protein contents and permitted the cells to rely on their mitochondrial ATP production to grow in the absence of glucose. In parallel to mtDNA increase, the presence of pVHL up regulated the mitochondrial transcription factor A, as shown by western blot analysis. In conclusion, in CCRCs, pVHL deficiency is one of the factors responsible for down-regulation of the biogenesis of OXPHOS complexes.

Adenosine Triphosphate↗
PubMed1995

Nuclear DNA origin of cytochrome c oxidase deficiency in Leigh's syndrome: genetic evidence based on patient's-derived rho degrees transformants.

Defects of the respiratory chain carrying out oxidative phosphorylation (OXPHOS) are the biochemical hallmark of human mitochondrial disorders. Faulty OXPHOS can be due to mutations in either nuclear or mitochondrial genes, that are involved in the synthesis of individual respiratory subunits or in their post-translational control. The most common mitochondrial disorder of infancy and childhood is Leigh's syndrome, a severe encephalopathy, often associated with a defect of cytochrome c oxidase (COX). In order to demonstrate which genome is primarily involved in COX-deficient (COX(-))-Leigh's syndrome, we generated two lines of transmitochondrial cybrids. The first was obtained by fusing nuclear DNA-less cytoplasts derived from normal fibroblasts, with mitochondrial DNA-less (rho degree) transformant fibroblasts derived from a patient with COX(-))-Leigh's syndrome. The second cybrid line was obtained by fusing rho degree cells derived from 143B.TK- human osteosarcoma cells, with cytoplasts derived from the same patient. The first cybrid line showed a specific and severe COX(-) phenotype, while in the second all the respiratory chain complexes, including COX, were normal. These results indicate that the COX defect in our patient is due to a mutation of a nuclear gene. The use of cybrids obtained from 'customized', patient-derived rho degree cells can have wide applications in the identification of respiratory chain defects originated by nuclear DNA-encoded mutations, and in the study of nuclear DNA-mitochondrial DNA interactions.

Cell Line↗