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PubMed2001

The effects of cytoplasmic transfer of mtDNA in relation to whole-body endurance performance.

The purpose of this study was to examine the relation between whole-body aerobic capacity and mitochondrial facilities. The mitochondrial enzyme system of oxidative phosphorylation (OXPHOS) is encoded both by mitochondrial DNA (mtDNA) and nuclear DNA. To identify the effect of mtDNA on whole-body aerobic capacity, we fused the platelets of the study subjects that contained mtDNA but that lacked nuclear DNA with rho(0) HeLa cells, which lacked mtDNA, and isolated repopulated cybrids. The mitochondrial respiratory functions of the cybrids, estimated from cell oxygen consumption and cytochrome-c oxidase (CCOX), were compared between endurance athletes and sedentary controls. The oxygen consumption was 18.5 +/- 3.9 and 18.2 +/- 4.1 nmol/min/ml/10(7) cells in athletes and controls, respectively. The CCOX activity was 98.8 +/- 17.5 and 116.7 +/- 9.8%, compared with fibroblasts in athletes and controls, respectively. No significant difference was noted between groups in either cell oxygen consumption or CCOX activity. These results show that the OXPHOS enzymes coded by mtDNA do not strongly influence whole-body aerobic fitness.

Adult↗
PubMed2006

Multiregional gene expression profiling identifies MRPS6 as a possible candidate gene for Parkinson's disease.

Combining large-scale gene expression approaches and bioinformatics may provide insights into the molecular variability of biological processes underlying neurodegeneration. To identify novel candidate genes and mechanisms, we conducted a multiregional gene expression analysis in postmortem brain. Gene arrays were performed utilizing Affymetrix HG U133 Plus 2.0 gene chips. Brain specimens from 21 different brain regions were taken from Parkinson's disease (PD) (n = 22) and normal aged (n = 23) brain donors. The rationale for conducting a multiregional survey of gene expression changes was based on the assumption that if a gene is changed in more than one brain region, it may be a higher probability candidate gene compared to genes that are changed in a single region. Although no gene was significantly changed in all of the 21 brain regions surveyed, we identified 11 candidate genes whose pattern of expression was regulated in at least 18 out of 21 regions. The expression of a gene encoding the mitochondria ribosomal protein S6 (MRPS6) had the highest combined mean fold change and topped the list of regulated genes. The analysis revealed other genes related to apoptosis, cell signaling, and cell cycle that may be of importance to disease pathophysiology. High throughput gene expression is an emerging technology for molecular target discovery in neurological and psychiatric disorders. The top gene reported here is the nuclear encoded MRPS6, a building block of the human mitoribosome of the oxidative phosphorylation system (OXPHOS). Impairments in mitochondrial OXPHOS have been linked to the pathogenesis of PD.

Adult↗
PubMed2005

Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors.

Reactive oxygen species (ROS) signal cascades involved in cell growth, cell death, mitogenesis, angiogenesis and carcinogenesis. ROS are produced as a byproduct of oxidative phosphorylation (OXPHOS) in the mitochondria. It is estimated that 2-4% of the oxygen consumed during OXPHOS is converted to ROS. Besides mitochondria, NADPH-oxidase 1 (Nox1) also generates a significant amount of ROS in the cell. In this paper, we tested the hypothesis that mitochondria control Nox 1 redox signaling and the loss of control of this signaling contributes to tumorigenesis. We analyzed Nox1 expression in a mitochondrial gene knockout (rho(0)) cell line and in the isogenic cybrid cell line in which mitochondrial genes were restored by transfer of wild type mitochondria into rho(0) cells. Our study revealed, for the first time, that the inactivation of mitochondrial genes leads to down-regulation of Nox1 and that the transfer of wild type mitochondrial genes restored the Nox1 expression to a level comparable to that in the parental cell line. Consistent with Nox1 down-regulation, we found that rho(0) cells contained low levels of superoxide anion and that superoxide levels reversed to parental levels in cybrid cells when Nox1 expression was restored by transfer of wild type mitochondria. Increasing mitochondrial superoxide levels also increased the expression of Nox1 in parental cells. Confocal microscopy studies revealed that Nox1 localizes in the mitochondria. Nox1 was highly expressed in breast (86%) and ovarian (71%) tumors and that its expression positively correlated with expression of cytochrome C oxidase encoded by mtDNA. Our study, described in this paper demonstrates the existence of cross talk between the mitochondria and NADPH oxidase. Furthermore, our studies suggest that mitochondria control Nox1 redox signaling and the loss of control of this signaling contributes to breast and ovarian tumorigenesis.

Breast Neoplasms↗
PubMedDate not supplied

[Recent advances in genetics of epilepsy. Genetic of mitochondrial epilepsy].

INTRODUCTION: Recently the molecular basis of a series of clinical disorders associated with defects in the oxidative phosphorylation system (OXPHOS system) leading to ATP synthesis, the final pathway of mitochondrial energy metabolism, has been established. The polypeptide components of the OXPHOS system are codified in both nuclear and mitochondrial DNA. Therefore these mitochondrial diseases may be originated by mutations of genes found in both genetic systems. DEVELOPMENT: In recent years, several such neuromuscular diseases have been defined and associated with mitochondrial DNA mutations. One of the most striking of these is the syndrome of myoclonic epilepsy with ragged red fibres (MERRF), characterized by myoclonic epilepsy of maternal inheritance. This disorder is caused by a specific mutation on the mitochondrial tRNA(Lys) (position 8344), which gives rise to a reduction in the level of lysil-tRNA(Lys) and thus to premature termination of the translation of proteins codified in the mitochondrial DNA.

DNA, Mitochondrial↗
PubMedDate not supplied

[Genetic diseases of the mitochondrial DNA in humans].

Mitochondrial diseases are a group of disorders produced by defects in the oxidative phosphorylation system (Oxphos system), the final pathway of the mitochondrial energetic metabolism, resulting in a deficiency of the biosynthesis of ATP. Part of the polypeptide subunits involved in the Oxphos system are codified by the mitochondrial DNA. In the last years, mutations in this genetic system have been described and associated to well defined clinical syndromes. The clinical features of these disorders are very heterogeneous affecting, in most cases, to different organs and tissues and their correct diagnosis require precise clinical, morphological, biochemical and genetic data. The peculiar genetic characteristics of the mitochondrial DNA (maternal inheritance, polyplasmia and mitotic segregation) give to these disorders very distinctive properties. The English version of this paper is available at: http://www.insp.mx/salud/index.html.

Adenosine Triphosphate↗
PubMed2001

[The research progress of the association of mitochondrial DNA mutation with cardiomyopathy].

There are some human diseases associated with mitochondrial DNA genome defect. Now many studies think that: oxygen radical resulting from oxidative phosphorylation(OXPHOS) disorder caused by myocardium ischemia and the increased OXPHOS induction damage mitochondrial DNA. Chronic damage accumulations lead to mitochondrial DNA deletion or point mutation in the end which show mitochondrial DNA 5.0 kb or 7.4 kb deletion and point mutation at position C15452A in the cytochrome b gene; the conservative sequence mutation of tRNA gene such as A4300G, C4320T point mutation in the tRNA Ilegene, A3243G point mutation in the tRNA leu gene etc result in defective contractile proteins whose persistent and inefficient contraction may increase the myocardium's metabolic demands for ATP and leads to cardiac hypertrophy. In this article, we review the study on the association of mitochondrial DNA mutation with ischemic cardiomyopathy and hypertrophic cardiomyopathy.

Cardiomyopathy, Hypertrophic↗
PubMed1992

Transcriptional control of nuclear genes for the mitochondrial muscle ADP/ATP translocator and the ATP synthase beta subunit. Multiple factors interact with the OXBOX/REBOX promoter sequences.

The OXBOX promoter regions of the genes for the muscle-specific adenine nucleotide translocator (ANT1) and the beta subunit of the ATPsynthase (ATPsyn beta) have been implicated in the increased transcription of these nuclear-encoded oxidative phosphorylation (OXPHOS) genes in heart and skeletal muscle. DNA binding, electrophoretic mobility shift (gel-shift) assays now reveal that the OXBOX region has two unique but overlapping elements, the 13-base pair (bp) OXBOX and an 8-bp REBOX. The OXBOX binding factors are found only in myogenic cell lines, whereas the REBOX factors are ubiquitous. Methylation interference experiments have defined the boundaries of the OXBOX and REBOX elements, confirmed that the OXBOX factors are muscle-specific, and shown that the OXBOX and REBOX factors do not bind concurrently. The binding of the REBOX factors was found to be sensitive to NADH and thyroxine, suggesting that it may modulate OXPHOS gene expression in response to environmental and hormonal changes. Hence, the OXBOX/REBOX complex provides one mechanism by which mammalian energy metabolism can be adapted to developmental and environmental demands.

Animals↗
PubMed2003

Review: Mitochondrial medicine--cardiomyopathy caused by defective oxidative phosphorylation.

During experimental hypertensive cardiac hypertrophy, the heart energy metabolism reverts from the normal adult type that obtains the majority of its requirement for adenosine triphosphate (ATP) from metabolism of fatty acids and oxidative phosphorylation (OXPHOS), to the fetal form, which metabolizes glucose and lactate. Mitochondrial synthesis and function require an estimated 1000 polypeptides, 37 of which are encoded by mitochondrial (mt) DNA, the rest by nuclear (n) DNA. Inherited or acquired aberrations of either mtDNA or nDNA mitochondrial genes cause mitochondrial dysfunction. Tissue expression of OXPHOS enzyme defects is often heterogeneous. As a result, cardiomyopathy and cardiac failure are frequent but unpredictable complications of mitochondrial encephalopathy, neuropathy, and myopathy. Several nuclear genes that encode mitochondrial proteins have been sequenced and specific defects associated with nuclear genes that affect mitochondrial structure and function have been linked to hypertrophic and dilated cardiomyopathies and to cardiac conduction defects. Thyroid hormone and exercise stimulate expression of a nuclear respiratory factor (NRF) that induces the nuclear gene TFAM, which encodes the mitochondrial transcription factor A that controls mitochondrial replication and transcription. TFAM-null mouse embryos lack mitochondria and fail to develop a heart. Mitochondrial dysfunction enhances the generation of radical oxygen species (ROS), which damage mtDNA, nDNA, proteins, and lipid membranes. Mice lacking the mitochondrial antioxidant enzyme manganese-superoxide dismutase (SOD) develop dilated cardiomyopathy. Palliative mitochondrial therapy with L-acetyl-carnitine and coenzyme Q10 improves cardiac function in patients with cardiomyopathy. Cure is only achievable by mitochondrial gene therapy. Experimental direct gene therapy uses vectors or targeting signal sequences to insert genes into mtDNA; indirect gene therapy employs viral or non-viral vectors to introduce genes into nDNA. Clinical repair of damaged somatic and germline genes that encode mitochondrial proteins may soon be within reach.

Animals↗
PubMed1990

Neoplastic transformation is associated with coordinate induction of nuclear and cytoplasmic oxidative phosphorylation genes.

Neoplastic transformation was found to have a marked effect on the expression of nuclear DNA (nDNA)- and mitochondrial DNA (mtDNA)-encoded oxidative phosphorylation (OXPHOS) genes. Examining three pairs of human diploid fibroblasts and their SV 40-transformed counterparts revealed that mRNAs for the nuclear-encoded ATP synthase beta and the adenine nucleotide translocator (ANT) isoform 1 and 2 genes were markedly induced, whereas the mRNA for the ANT isoform 3 gene remained unchanged. The mRNA levels for the mtDNA-encoded 12 S rRNA, ND2, ATPase6+8, COIII, ND5+6, and Cytb genes were also increased, whereas the mtDNA number declined. Similar analysis of a cervical carcinoma (HeLa), fibrosarcoma (HT1080), and an Epstein-Barr virus (EBV)-transformed lymphoblastoid line (EBV-L) revealed that all three ANT isoforms were also expressed in these cells. Hence, changes in the expression of OXPHOS genes may be a common feature of transformed cells.

Base Sequence↗
PubMedDate not supplied

Adverse effects of nonsteroidal anti-inflammatory drugs on the gastrointestinal system.

Two enzymes, cyclo-oxygenase (COX) and 5-lipoxygenase, act upon arachidonic acids to produce prostaglandins and leukotrienes. Inhibition of COX-2 by non-steroidal anti-inflammatory drugs (NSAIDs) lowers synthesis of proinflammatory prostaglandins and produces analgesia. COX-2 is highly inducible by endotoxin, IL-1, hypoxia, epidermal growth factor (EGF), benzo[a]pyrene, and transforming growth factor beta 1(TGF-beta 1). COX-1 in constitutively expressed. Conventional NSAIDs also inhibit the synthesis of cytoprotective prostaglandins by COX-1 in the gastrointestinal tract. Surplus arachidonic acids accumulate and enhance the generation of leukotrienes via the lipoxygenase pathway inducing neutrophil adhesion to endothelium and vasoconstriction. The NSAIDs harboring a carboxyl group also inhibit oxidative phosphorylation (OXPHOS) lowering adenosine-triphosphate (ATP) generation leading to loss of mucosal cell tight junctions and increased mucosal permeability. Administration of NSAIDs that do not interfere with OXPHOS, and concomitant use of prostaglandin analogues to restore cytoprotection reduces complications of NSAID use. However, no NSAID that lacks potential for serious gastrointestinal toxicity is currently available. Selective inhibitors of COX-2 and 5-lipoxygenase are newer, promising drugs. Surprisingly, COX-2 null mice are able to mount an inflammatory response, suffering however, from kidney dysfunction and a shortened life span. Results of clinical studies on the long-term use of NSAID drugs such as selective inhibitors are still pending.

Aging↗
PubMed1998

Inborn and induced defects of mitochondria.

Mitochondria play a pivotal role in cellular metabolism and in energy production in particular. Predictably, defects of mitochondrial metabolism have a deleterious effect on cell function and survival, especially in highly energy-dependent tissues such as brain and skeletal muscle. Although a multitude of biochemical reactions occur within mitochondria, the oxidative phosphorylation (OXPHOS) system is the most important in terms of adenosine triphosphate generation and in its association with human disease.

DNA, Mitochondrial↗
PubMed2000

Isolated complex I deficiency in children: clinical, biochemical and genetic aspects.

We retrospectively examined clinical and biochemical characteristics of 27 patients with isolated enzymatic complex I deficiency (established in cultured skin fibroblasts) in whom common pathogenic mtDNA point mutations and major rearrangements were absent. Clinical phenotypes present in this group are Leigh syndrome (n = 7), Leigh-like syndrome (n = 6), fatal infantile lactic acidosis (n = 3), neonatal cardiomyopathy with lactic acidosis (n = 3), macrocephaly with progressive leukodystrophy (n = 2), and a residual group of unspecified encephalomyopathy (n = 6) subdivided into progressive (n = 4) and stable (n = 2) variants. Isolated complex I deficiency is one of the most frequently observed disturbance of the OXPHOS system. Respiratory chain enzyme assays performed in cultured fibroblasts and skeletal muscle tissue in general reveal similar results, but for complete diagnostics we recommend enzyme measurements performed in at least two different tissues to minimize the possibility of overlooking the enzymatic diagnosis. Lactate levels in blood and CSF and cerebral CT/MRI studies are highly informative, although normal findings do not exclude complex I deficiency. With the discovery of mutations in nuclear encoded complex I subunits, adequate pre- and postnatal counseling becomes available. Finally, considering information currently available, isolated complex I deficiency in children seems to be caused in the majority by mutations in nuclear DNA.

Child↗
PubMed2001

Mouse models for mitochondrial disease.

Mutations in mitochondrial genes encoded by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes have been implicated in a wide range of neuromuscular diseases. MtDNA base substitution and rearrangement mutations generally inactivate one or more tRNA or rRNA genes and can cause myopathy, cardiomyopathy, cataracts, growth retardation, diabetes, etc. nDNA mutations can cause Leigh syndrome, cardiomyopathy, and nephropathy, due to defects in oxidative phosphorylation (OXPHOS) enzyme complexes; cartilage-hair hypoplasia (CHH) and mtDNA depletion syndrome, through defects in mitochondrial nucleic acid metabolism; and ophthalmoplegia with multiple mtDNA deletions, caused by adenine nucleotide translocator-1 (ANT1) mutations. Mouse models have been prepared that recapitulate a number of these diseases. The mtDNA 16S rRNA chloramphenicol (CAP) resistance mutation was introduced into the mouse female germline and caused cataracts and rod and cone abnormalities in chimeras and neonatal lethal myopathy and cardiomyopathy in mutant animals. A mtDNA deletion was introduced into the mouse germline and caused myopathy, cardiomyopathy, and nephropathy. Conditional inactivation of the nDNA mitochondrial transcription factor (Tfam) gene in the heart resulted in neonatal lethal cardiomyopathy, while its inactivation in the pancreatic beta-cells caused diabetes. The ATP/ADP ratio was implicated in mitochondrial diabetes through transgenic modification of the beta-cell ATP-sensitive K(+) channel (K(ATP)). Mutational inactivation of the mouse Ant1 gene resulted in myopathy, cardiomyopathy, and multiple mtDNA deletions in association with elevated reactive oxygen species (ROS) production. Inactivation of uncoupler proteins (Ucp) 1-3 revealed that mitochondrial Delta Psi regulated ROS production. The role of mitochondrial ROS toxicity in disease and aging was confirmed by inactivating glutathione peroxidase (GPx1), resulting in growth retardation, and by total and partial inactivation of Mn superoxide dismutase (MnSOD; Sod2), resulting in neonatal lethal dilated cardiomyopathy and accelerated apoptosis in aging, respectively. The importance of mitochondrial ROS in degenerative diseases and aging was confirmed by treating Sod2 -/- mice and C. elegans with catalytic antioxidant drugs.

Animals↗
PubMed1994

Marked changes in mitochondrial DNA deletion levels in Alzheimer brains.

Levels of the common 4977 nucleotide pair (np) mitochondrial DNA (mtDNA) deletion (mtDNA4977) were quantitated in the cortex, putamen, and cerebellum of patients with Alzheimer disease (AD) and compared to age-matched controls. Although cerebellum deletion levels were comparably low in AD patients and controls of all ages, cortical deletion levels were clearly different. The levels of mtDNA deletions in control brains started low, but rose markedly after age 75, while those of AD patients started high and declined to low levels by age 80. Choosing age 75 to arbitrarily delineate between younger and older subjects, younger patients had 15 times more mtDNA deletions than younger controls, while older patients had one-fifth the deletion level of older controls. Younger AD patients also had fourfold more deletions than older AD patients. These results support the hypothesis that OXPHOS defects resulting from somatic mtDNA mutations may play a role in AD pathophysiology.

Age Factors↗
PubMed2003

Mitochondrial regulation by melatonin and its metabolites.

Our results show that melatonin and N-acetyl-5-methoxykynurenamine (aMK) physiologically regulate both the electron transport chain (ETC) and OXPHOS, increasing the electron transport and ATP synthesis by normal mitochondria. Melatonin also counteracts mitochondrial oxidative damage induced by t-butyl hydroperoxide, recovering glutathione levels and ATP production. However, the effects of melatonin not only depend of its antioxidant properties, since the indoleamine specifically interacts with complex I and IV of the ETC increasing their activity. Experiments in vivo showed that melatonin administration prevents sepsis-induced ETC damage decreasing the activity and expression of INOS and mtNOS, thus reducing intramitochondrial nitric oxide (NO) and peroxynitrite (ONOO-) levels. Consequently, mitochondrial ETC ad ATP production recovered to normal conditions. The presence of specific binding of melatonin in mitochondrial matrix led us to explore the genomic role of the indoleamine in these organelles. In vivo and in vitro experiments showed that administration of melatonin increased mtONA transcriptional activity of the subunits 1-3 of the complex IV. These effects correlated well with the effects of melatonin on complex IV activity. The data suggest a new rate for melatonin to regulate mitochondrial homeostasis. Due to the relationships between mitochondrial damage, aging and neurodegenerative diseases, the effects of melatonin here described further support its antiaging and neuroprotective properties.

Adenosine Triphosphate↗
PubMed2004

Neurodegenerative disorders associated with diabetes mellitus.

More than 20 syndromes among the significant and increasing number of degenerative diseases of neuronal tissues are known to be associated with diabetes mellitus, increased insulin resistance and obesity, disturbed insulin sensitivity, and excessive or impaired insulin secretion. This review briefly presents such syndromes, including Alzheimer disease, ataxia-telangiectasia, Down syndrome/trisomy 21, Friedreich ataxia, Huntington disease, several disorders of mitochondria, myotonic dystrophy, Parkinson disease, Prader-Willi syndrome, Werner syndrome, Wolfram syndrome, mitochondrial disorders affecting oxidative phosphorylation, and vitamin B(1) deficiency/inherited thiamine-responsive megaloblastic anemia syndrome as well as their respective relationship to malignancies, cancer, and aging and the nature of their inheritance (including triplet repeat expansions), genetic loci, and corresponding functional biochemistry. Discussed in further detail are disturbances of glucose metabolism including impaired glucose tolerance and both insulin-dependent and non-insulin-dependent diabetes caused by neurodegeneration in humans and mice, sometimes accompanied by degeneration of pancreatic beta-cells. Concordant mouse models obtained by targeted disruption (knock-out), knock-in, or transgenic overexpression of the respective transgene are also described. Preliminary conclusions suggest that many of the diabetogenic neurodegenerative disorders are related to alterations in oxidative phosphorylation (OXPHOS) and mitochondrial nutrient metabolism, which coincide with aberrant protein precipitation in the majority of affected individuals.

Animals↗
PubMed2025

Integrating multi-omics approaches in acute myeloid leukemia (AML): Advancements and clinical implications.

Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive hematologic malignancy characterized by clonal proliferation of myeloid precursors. Despite significant advancements in genomic profiling and targeted therapies, patient outcomes remain suboptimal due to disease complexity, resistance mechanisms, and high relapse rates. The integration of multi-omics approaches-spanning genomics, epigenomics, transcriptomics, proteomics, and metabolomics-has revolutionized AML research, offering a comprehensive understanding of leukemogenesis, tumor heterogeneity, and therapeutic vulnerabilities. Recent studies leveraging high-throughput sequencing, mass spectrometry, and advanced computational tools have uncovered novel biomarkers, clonal evolution dynamics, and microenvironmental interactions that drive AML progression and resistance. For instance, single-cell multi-omics has revealed chemotherapy-resistant leukemic stem cell populations, while proteogenomic analyses have identified actionable targets such as MCL1 and metabolic dependencies like OXPHOS. Clinically, integrated omics platforms are refining risk stratification, minimal residual disease (MRD) monitoring, and personalized therapy selection. However, challenges such as data integration complexity, cost barriers, and ethical considerations remain. This review highlights the transformative potential of multi-omics in AML, emphasizing recent advancements in technology, biomarker discovery, and therapeutic innovation. By bridging the gap between molecular insights and clinical practice, multi-omics integration promises to redefine AML management, paving the way for precision oncology and improved patient outcomes.

Humans↗
PubMed2026

Association Between Ticagrelor and Glucose Homeostasis Regulation: Insights from Genetic and Transcriptomic Analyses.

Emerging evidence has demonstrated the additional therapeutic benefits of ticagrelor in acute coronary syndrome (ACS) patients with diabetes. However, the underlying mechanisms of this association remain elusive. Mendelian randomization (MR) analysis using genome-wide association study (GWAS) data on ticagrelor, plasma proteomics and type 2 diabetes was employed to identify causal mediator proteins. RNA sequencing (RNA-seq) of ticagrelor-treated HepG2 cells revealed the molecular pathways regulating glucose metabolism. Genetically proxied ticagrelor was significantly associated with a reduced risk of diabetes (OR = 0.859, 95% CI: 0.783-0.934, P = 7.98E-05), and 24.41% of this effect was mediated by upregulation of BDH2 protein. In vitro experiments confirmed the enhanced effect of ticagrelor on glucose consumption. Transcriptome analysis revealed that mitochondrial respiratory chain transfer and oxidative phosphorylation (OXPHOS) were significantly enriched, and genes related to ATP biosynthesis were significantly upregulated. These findings highlight the non-platelet function of ticagrelor in maintaining glucose homeostasis, providing insights into potential drug repurposing in the future.

Humans↗