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PubMed1996

Differential effects of creatine depletion on the regulation of enzyme activities and on creatine-stimulated mitochondrial respiration in skeletal muscle, heart, and brain.

Guanidinopropionic acid (GPA), an analogue of creatine (Cr), is known to inhibit Cr uptake by cells. The metabolic effects of chronic Cr depletion on brain, heart and soleus muscle of rats were studied. In GPA hearts and soleus muscle, total specific creatine kinase (CK) activity was decreased by approx. 40% compared to controls, whereas in brain this same activity was elevated by a factor of two. Immunoblot analysis of soleus mitochondria from GPA rats showed an approximate 4-fold increase in Mi-CK protein and a concomitant 3-fold increase in adenine nucleotide translocator (ANT) protein, when compared to control. In GPA-fed rats, the specific activities of adenylate kinase (ADK) and succinate dehydrogenase were significantly higher in brain and soleus (2-fold), but heart remained the same. However, hexokinase (HK) decreased by approx. 50% both in heart and soleus, indicating that muscle and brain follow different strategies to compensate the energy deficit caused by creatine depletion. Skinned muscle fibres from Cr-depleted soleus attained approx. only 70% maximum state 3 respiration with 0.1 M ADP in the presence of 10 mM Cr compared to 100% in control fibres. This defect in Cr stimulated respiration was also seen in isolated heart mitochondria, but was normal in those from brain. The observed deficit of Cr-stimulated respiration, the significant accumulation of Mib-CK and ANT, concomitant with the formation of Mib-CK rich intra-mitochondrial inclusions shown by electron microscopy, indicate that Mib-CK function and coupling to oxidative phosphorylation (OXPHOS), is impaired in these abnormal mitochondria. In addition, our results show tissue-specific metabolic compensations to Cr depletion.

Adaptation, Physiological↗
PubMed1995

Mitochondrial DNA mutations in human degenerative diseases and aging.

A wide variety of mitochondrial DNA (mtDNA) mutations have recently been identified in degenerative diseases of the brain, heart, skeletal muscle, kidney and endocrine system. Generally, individuals inheriting these mitochondrial diseases are relatively normal in early life, develop symptoms during childhood, mid-life, or old age depending on the severity of the maternally-inherited mtDNA mutation; and then undergo a progressive decline. These novel features of mtDNA disease are proposed to be the product of the high dependence of the target organs on mitochondrial bioenergetics, and the cumulative oxidative phosphorylation (OXPHOS) defect caused by the inherited mtDNA mutation together with the age-related accumulation mtDNA mutations in post-mitotic tissues.

Adult↗
PubMed1996

Coordinate expression of nuclear and mitochondrial genes involved in energy production in carcinoma and oncocytoma.

The expression of mitochondrial and nuclear genes involved in ATP production was examined in renal carcinomas, renal oncocytomas, and a salivary oncocytoma. Renal carcinomas were found to have a reduced mitochondrial DNA (mtDNA) content while oncocytomas had increased mtDNA contents. This parallels morphological changes in mitochondrial number in these tumours. In the carcinomas, mtDNA transcripts were decreased 5- to 10-fold relative to control kidneys, suggesting that mitochondrial transcript levels depend on the mtDNA content. In renal oncocytomas, mtDNA transcripts were slightly reduced in spite of a high mtDNA content. However, in the salivary gland oncocytoma, mtDNA transcripts were increased more than 10-fold in parallel with a 10-fold increase in mtDNA content. The expression of the nuclear DNA oxidative phosphorylation genes, ATPsyn beta and ANT2, was reduced up to 4-fold in renal carcinoma. In contrast, the levels of these two nuclear gene transcripts were induced about 4-fold in renal oncocytoma and up to 30-fold in salivary gland oncocytoma. Moreover, the ANT2 precursors were observed to change in oncocytomas. These data suggest a coordinated regulation of nuclear and mitochondrial gene expression in renal carcinomas and the specific induction of nuclear OXPHOS gene expression in oncocytomas.

Adenoma, Oxyphilic↗
PubMed2004

Clinical and molecular findings in children with complex I deficiency.

Isolated complex I deficiency, the most frequent OXPHOS disorder in infants and children, is genetically heterogeneous. Mutations have been found in seven mitochondrial DNA (mtDNA) and eight nuclear DNA encoded subunits, respectively, but in most of the cases the genetic basis of the biochemical defect is unknown. We analyzed the entire mtDNA and 11 nuclear encoded complex I subunits in 23 isolated complex I-deficient children, classified into five clinical groups: Leigh syndrome, progressive leukoencephalopathy, neonatal cardiomyopathy, severe infantile lactic acidosis, and a miscellaneous group of unspecified encephalomyopathies. A genetic definition was reached in eight patients (35%). Mutations in mtDNA were found in six out of eight children with Leigh syndrome, indicating a prevalent association between this phenotype and abnormalities in ND genes. In two patients with leukoencephalopathy, homozygous mutations were detected in two different nuclear-encoded complex I genes, including a novel transition in NDUFS1 subunit. In addition to these, a child affected by mitochondrial encephalomyopathy had heterozygous mutations in NDUFA8 and NDUFS2 genes, while another child with neonatal cardiomyopathy had a complex rearrangement in a single NDUFS7 allele. The latter cases suggest the possibility of unconventional patterns of inheritance in complex I defects.

Acidosis, Lactic↗
PubMed2005

Decreased agonist-stimulated mitochondrial ATP production caused by a pathological reduction in endoplasmic reticulum calcium content in human complex I deficiency.

Although a large number of mutations causing malfunction of complex I (NADH:ubiquinone oxidoreductase) of the OXPHOS system is now known, their cell biological consequences remain obscure. We previously showed that the bradykinin (Bk)-induced increase in mitochondrial [ATP] ([ATP](M)) is significantly reduced in primary skin fibroblasts from a patient with an isolated complex I deficiency. The present work addresses the mechanism(s) underlying this impaired response. Luminometry of fibroblasts from 6 healthy subjects and 14 genetically characterized patients expressing mitochondria targeted luciferase revealed that the Bk-induced increase in [ATP](M) was significantly, but to a variable degree, decreased in 10 patients. The same variation was observed for the increases in mitochondrial [Ca(2+)] ([Ca(2+)](M)), measured with mitochondria targeted aequorin, and cytosolic [Ca(2+)] ([Ca(2+)](C)), measured with fura-2, and for the Ca(2+) content of the endoplasmic reticulum (ER), calculated from the increase in [Ca(2+)](C) evoked by thapsigargin, an inhibitor of the ER Ca(2+) ATPase. Regression analysis revealed that the increase in [ATP](M) was directly proportional to the increases in [Ca(2+)](C) and [Ca(2+)](M) and to the ER Ca(2+) content. Our findings provide evidence that a pathological reduction in ER Ca(2+) content is the direct cause of the impaired Bk-induced increase in [ATP](M) in human complex I deficiency.

Adenosine Triphosphate↗
PubMed2025

Integrated multi-omics analysis reveals TMEM147 as an immunosuppressive prognostic biomarker in LUAD.

TMEM147, an endoplasmic reticulum (ER) membrane protein, is implicated in lung adenocarcinoma (LUAD) progression, although its precise role remains unclear. To elucidate its function, this study integrated bioinformatics analyses with experimental validation. First, TMEM147 expression was assessed using TCGA and GEO datasets, with validation performed in LUAD cell lines. Survival analysis evaluated its prognostic significance. Subsequently, Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and single-sample gene set enrichment analysis (ssGSEA) were employed to identify associated functional pathways and interactions within the tumor immune microenvironment. Transcription factor binding predictions and in vitro functional assays (migration, invasion, proliferation) further characterized TMEM147's role. Results indicated that TMEM147 was significantly upregulated in LUAD and correlated with poor outcomes in patients. FLI1 was predicted as a key transcriptional regulator of TMEM147. Furthermore, TMEM147 expression influenced immune cell infiltration profiles and was associated with pathways involved in ribonucleoprotein biogenesis and oxidative phosphorylation (OXPHOS). Importantly, silencing TMEM147 significantly reduced cancer cell migration, invasion, and proliferation. These findings collectively suggest that TMEM147 promotes LUAD progression and holds potential as both a prognostic biomarker and a therapeutic target.

Bioinformatics analysis↗
PubMed2005

The human mitochondrial proteome: oxidative stress, protein modifications and oxidative phosphorylation.

Mitochondria are one of the most complex of subcellular organelles and play key roles in many cellular functions including energy production, fatty acid metabolism, pyrimidine biosynthesis, calcium homeostasis, and cell signaling. In recent years, we and other groups have attempted to identify the complete set of proteins that are localized to human mitochondria as a way to better understand its cellular functions and how it communicates with other cell compartment in complex signaling pathways such as oxidative stress and apoptosis. Indeed, there is an increasing interest in understanding the molecular details of oxidative stress and the mitochondrial role in this process, as well as assessing how mitochondrial proteins become damaged or posttranslationally modified as a consequence of a major change in a cell's redox status. In this review, we report on the current status of the human mitochondrial proteome with an emphasis towards understanding how mitochondrial proteins, especially the proteins that make up the respiratory chain or oxidative phosphorylation (OXPHOS) enzymes, are modified in various models of age-related diseases such as cancer and Parkinson's disease (PD).

Cell Line, Tumor↗
PubMed2004

Analysis of the mitochondrial encoded subunits of complex I in 20 patients with a complex I deficiency.

NADH-ubiquinone oxidoreductase or complex I deficiency is a frequently diagnosed enzyme defect of the oxidative phosphorylation (OXPHOS) system in humans. However, in many patients, with complex I deficiency and clinical symptoms suggestive of mitochondrial disease, often no genetic defect can be found after investigation of the most common mitochondrial DNA (mtDNA) mutations. In this study, 20 patients were selected with a biochemically documented complex I defect and no common mtDNA mutation. We used the Denaturing Gradient Gel Electrophoresis (DGGE) method with primers encompassing all mitochondrial encoded fragments, to search in a systematic manner for mutations in the mitochondrial genome of complex I. In our group of patients, we were able to detect a total of 96 nucleotide changes. We were not able to find any disease causing mutation in the mitochondrial encoded subunits of complex I. These results suggested that the complex I deficiency in this group of patients is most probably caused by a defect in one of the nuclear encoded structural genes of complex I, or in one of the genes involved in proper assembly of the enzyme.

Age of Onset↗
PubMed2005

Tissue-specific changes of mitochondrial functions in aged rats: effect of a long-term dietary treatment with N-acetylcysteine.

The understanding of the involvement of mitochondrial oxidative phosphorylation (OXPHOS) in the aging process has often been biased by the different methodological approaches as well as the choice of the biological material utilized by the various groups. In the present paper, we have carried out a detailed analysis of several bioenergetic parameters and oxidative markers in brain and heart mitochondria from young (2 months) and old (28 months) rats. This analysis has revealed an age-related decrease in respiratory fluxes in brain but not in heart mitochondria. The age-related decrease in respiratory rate (-43%) by NAD-dependent substrates was associated with a consistent decline (-40%) of complex I activity in brain mitochondria. On the other hand, heart mitochondria showed an age-related decline of complex II activity. Both tissues showed, however, an age-associated accumulation of oxidative damage. We have then performed the same analysis on old (28 months) rats subjected to a long-term (16 months) diet containing the antioxidant N-acetylcysteine (NAC). The treated old rats showed a slight brain-specific improvement of mitochondrial energy production efficiency, mostly with NAD-dependent substrates, together with a decrease in carbonyl protein content and an increase in the amount of protein thiols of brain cytosolic fraction. A full recovery of complex II activity was detected in heart mitochondria from NAC-treated old rats. The present work documents the marked tissue specificity of the decline of bioenergetic functions in isolated mitochondria from aged rats and provides the first data on the effects of a long-term treatment with N-acetylcysteine.

Acetylcysteine↗
PubMed2005

Differences of sperm motility in mitochondrial DNA haplogroup U sublineages.

We had previously shown that sperm from men harbouring haplogroup T mtDNAs swim less vigorously than those from haplogroup H. However, the biochemical basis of this motility was difficult to investigate because of the multiple mutations, the most important of which affected respiratory complex I for which there is no crystal structure. To more thoroughly study the relationship between mtDNA variation and differences in mitochondrial energy metabolism, we turned to the analysis of sperm baring haplogroup U mtDNAs. Haplogroup U is a monophyletic ancient and thus heterogeneous maternal lineage that is broadly distributed among European individuals. Several sublineages of haplogroup U were found to be associated with differences in sperm motility and vitality. These differences could be related to a highly conserved missense mutation in the mtDNA COIII gene (V91) and several equally conserved mutations in the cytochrome b (cytb) gene. Moreover, the lineages with the cytb mutations were substantially enriched in northern Europe, while those lacking these mutations were more prevalent in southern Europe. We suggest that some of these ancient conserved cytb missense mutations permitted our ancestors to adapt to cold by partially uncoupling mitochondrial oxidative phosphorylation (OXPHOS).

Adult↗
PubMed2004

Immunological approaches to the characterization and diagnosis of mitochondrial disease.

Monoclonal antibodies (mAbs) are important tools in the diagnosis and characterization of mitochondrial diseases. They can be used in immunohistochemical and/or Western blotting approaches to identify misassembled OXPHOS complexes or pyruvate dehydrogenase deficiencies where the intact complex is not formed which is the great majority of cases. The advantage of antibody based approaches is that they can be quantitative, require very small amounts of tissue sample and are fast, simple and relatively cheap to perform. Here we provide details of the mAbs currently available and describe optimized protocols for both immunohistochemistry using patient fibroblasts as well as Western blotting using either cell culture or biopsy material.

Journal Article↗
PubMed2004

The neurological presentations of childhood and adult mitochondrial disease: established syndromes and phenotypic variations.

Mitochondrial disorders are caused by mutations of nuclear or mitochondrial DNA encoded genes involved in oxidative phosphorylation (OXPHOS). Mutations in these critical genes are associated with specific clinical syndromes with diverse presentations (DiMauro and Schon, 2003. NEJM 348, 2656; Hart et al., 2002. Mitochondrial Disorders in Neurology). Since mitochondria are present in many of our organs and play a key role in energy metabolism, mitochondrial encephalomyopathies often present as multisystem disorders which may manifest with neurologic, cardiac, endocrine, gastrointestinal, hepatic, renal and/or hematologic involvement (DiMauro and Bonilla, 1997. The Molecular and Genetic Basis of Neurological Disease; Vu et al., 2002. Neurol. Clin. N. Am. 20, 809). This chapter will address adult and childhood onset mitochondrial DNA encephalomyopathies, characteristic clinical presentations, as well as their molecular characterization.

Journal Article↗
PubMed2006

The F(1)F(0) ATP synthase and mitochondrial respiratory chain complexes are present on the plasma membrane of an osteosarcoma cell line: An immunocytochemical study.

F(1)F(0) ATP synthase is ectopically expressed on the surface of several cell types, including endothelium and cancer cells. This study uses immunocytochemical detection methods via highly specific monoclonal antibodies to explore the possibility of plasma membrane localization of other mitochondrial proteins using an osteosarcoma cell line in which the location of the mitochondrial reticulum can be clearly traced by green fluorescent protein tagging of the organelle. We found that subunits of three of the four respiratory chain complexes were present on the surface of these cells. Additionally, we show for the first time that F(0) subunits d and OSCP of the ATP synthase are ectopically expressed. In all cases the OXPHOS proteins show a punctate distribution, consistent with data from proteome analysis of isolated lipid rafts that place the various mitochondrial proteins in plasma membrane microdomains. We also examined the cell surface for marker membrane proteins from several other intracellular organelles including ER, golgi and nuclear envelope. They were not found on the surface of the osteosarcoma cells. We conclude that mitochondrial membrane proteins are ectopically expressed, but not proteins from other cellular organelles. A specific mechanism by which the mitochondrion and plasma membrane fuse to deliver organellar proteins is suggested.

Cell Line, Tumor↗
PubMed2026

Oxidative stress and cancer: current insights and therapeutic implications.

OXIDATIVE STRESS: good or evil? Oxidative stress occurs when the balance between reactive oxygen species (ROS) and antioxidant defenses shifts toward an excess of ROS; while essential in physiological processes, it plays a context-dependent role in cancer, contributing to both the promotion and inhibition of tumorigenesis. Small to moderate amounts of ROS activate pathways supporting tumor progression and proliferation, while large amounts lead to genomic instability and cell death. ROS are generated endogenously and exogenously. In cancer, ROS activate pathways that prompt tumor development (KRAS, MYC, PI3K-Akt-mTOR) and block tumor suppressors (p53, BRCA1), allowing tumorigenesis and drug resistance. They also modulate the tumor microenvironment (TME) by altering tumor, stromal and immune cell interactions, which initiate angiogenesis, epithelial-mesenchymal transition (EMT), inflammation and metastasis. Myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs) contribute to ROS-driven immunosuppression. Cancer cells mainly rely on glycolysis and oxidative phosphorylation (OXPHOS) to sustain their energetic and metabolic requirements. Generated ROS act as metabolic byproducts and signaling molecules supporting proliferation and tumorigenesis. Cancer stem cells (CSCs) produce low ROS levels by activating antioxidant pathways and mitochondria remodeling, ensuring recurrence and persistence. There is a redox duality that presents challenges and opportunities for therapies. Pro-oxidant approaches attempt to overwhelm the tumor's defenses, while antioxidants preserve healthy tissues. Advances in targeted redox modulation with immunotherapies improve therapy effectiveness. We propose a new "Adaptive Directed Redox Therapy" (ADRT), which involves a dynamic, feedback-controlled methodology that alternates pro- and antioxidant phases to selectively collapse tumor redox balance while preserving normal tissues.

Humans↗
PubMed2026

Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.

High metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to therapy resistance, necessitating identification of therapeutic vulnerabilities. Here, we identify non-canonical functions of the extracellular matrix (ECM) remodeler, lysyl oxidase (LOX), in regulating glucose metabolism and mitochondrial homeostasis and show that inhibiting LOX generates targetable vulnerability to ferroptosis. Mechanistically, LOX interacts with PARKIN and its upstream kinase PINK1, which we identified as a substrate of LOX. LOX-mediated PINK1 oxidation suppresses PARKIN phosphorylation, stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) and increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and maintains mitochondria-ER contacts through VDAC1 stabilization, while the LOX-HSP90 complex promotes mitochondrial Ca2+ transport and ATP production. Inhibiting LOX suppresses glycolysis, disrupts mitochondrial dynamics, reduces OXPHOS and GPX4/FSP1, and induces compensatory DHODH activity. Our "one-two punch" approach combining LOX inhibition with clinical DHODH inhibitor suppresses tumor growth in vivo in chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in TNBC patient tumors, supporting its clinical relevance.

Ferroptosis↗
PubMed2004

Cofactor treatment improves ATP synthetic capacity in patients with oxidative phosphorylation disorders.

Marked progress has been made over the past 15 years in defining the specific biochemical defects and underlying molecular mechanisms of oxidative phosphorylation disorders, but limited information is currently available on the development and evaluation of effective treatment approaches. Metabolic therapies that have been reported to produce a positive effect include coenzyme Q(10) (ubiquinone), other antioxidants such as ascorbic acid and vitamin E, riboflavin, thiamine, niacin, vitamin K (phylloquinone and menadione), and carnitine. The goal of these therapies is to increase mitochondrial ATP production, and to slow or arrest the progression of clinical symptoms. In the present study, we demonstrate for the first time that there is a significant increase in ATP synthetic capacity in lymphocytes from patients undergoing cofactor treatment. We also examined in vitro cofactor supplementation in control lymphocytes in order to determine the effect of the individual components of the cofactor treatment on ATP synthesis. A dose-dependent increase in ATP synthesis with CoQ(10) incubation was demonstrated, which supports the proposal that CoQ(10) may have a beneficial effect in the treatment of oxidative phosphorylation (OXPHOS) disorders.

Adenosine Triphosphate↗
PubMed2002

Mitochondrial DNA somatic mutations (point mutations and large deletions) and mitochondrial DNA variants in human thyroid pathology: a study with emphasis on Hürthle cell tumors.

In an attempt to progress in the understanding of the relationship of mitochondrial DNA (mtDNA) alterations and thyroid tumorigenesis, we studied the mtDNA in 79 benign and malignant tumors (43 Hürthle and 36 non-Hürthle cell neoplasms) and respective normal parenchyma. The mtDNA common deletion (CD) was evaluated by semiquantitative polymerase chain reaction. Somatic point mutations and sequence variants of mtDNA were searched for in 66 tumors (59 patients) and adjacent parenchyma by direct sequencing of 70% of the mitochondrial genome (including all of the 13 OXPHOS system genes). We detected 57 somatic mutations, mostly transitions, in 34 tumors and 253 sequence variants in 59 patients. Follicular and papillary carcinomas carried a significantly higher prevalence of non-silent point mutations of complex I genes than adenomas. We also detected a significantly higher prevalence of complex I and complex IV sequence variants in the normal parenchyma adjacent to the malignant tumors. Every Hürthle cell tumor displayed a relatively high percentage (up to 16%) of mtDNA CD independently of the lesion's histotype. The percentage of deleted mtDNA molecules was significantly higher in tumors with D-loop mutations than in mtDNA stable tumors. Sequence variants of the ATPase 6 gene, one of the complex V genes thought to play a role in mtDNA maintenance and integrity in yeast, were significantly more prevalent in patients with Hürthle cell tumors than in patients with non-Hürthle cell neoplasms. We conclude that mtDNA variants and mtDNA somatic mutations of complex I and complex IV genes seem to be involved in thyroid tumorigenesis. Germline polymorphisms of the ATPase 6 gene are associated with the occurrence of mtDNA CD, the hallmark of Hürthle cell tumors.

Adenoma, Oxyphilic↗
PubMed2007

Nuclear transfer: preservation of a nuclear genome at the expense of its associated mtDNA genome(s).

Nuclear transfer technology has uses across theoretical and applied applications, but advances are restricted by continued poor success rates and health problems associated with live offspring. Development of reconstructed embryos is dependent upon numerous interlinking factors relating both to the donor cell and the recipient oocyte. For example, abnormalities in gene expression following somatic cell nuclear transfer (SCNT) have been linked with an inability of the oocyte cytoplasm to sufficiently epigenetically reprogram the nucleus. Furthermore, influences on the propagation of mitochondria and mitochondrial DNA (mtDNA) could be of great importance in determining the early developmental potential of NT embryos and contributing to their genetic identity. mtDNA encodes some of the subunits of the electron transfer chain, responsible for cellular ATP production. The remaining subunits and those factors required for mtDNA replication, transcription and translation are encoded by the nucleus, necessitating precise intergenomic communication. Additionally, regulation of mtDNA copy number, via the processes of mtDNA transcription and replication, is essential for normal preimplantation embryo development and differentiation. Unimaternal transmission following natural fertilization usually results in the presence of a single identical population of mtDNA, homoplasmy. Heteroplasmy can result if mixed populations of mtDNA genomes co-exist. Many abnormalities observed in NT embryos, fetuses, and offspring may be caused by deficiencies in OXPHOS, perhaps resulting in part from heteroplasmic mtDNA populations. Additionally, incompatibilities between the somatic nucleus and the cytoplast may be exacerbated by increased genetic divergence between the two genomes. It is important to ensure that the nucleus is capable of sufficiently regulating mtDNA, requiring a level of compatibility between the two genomes, which may be a function of evolutionary distance. We suggest that abnormal expression of factors such as TFAM and POLG in NT embryos will prematurely drive mtDNA replication, hence impacting on early development.

Adaptation, Biological↗