Le encefalomiopatie mitocondriali

The mitochondrial encephalomyopathies are relatively rare neuromuscular diseases clinically characterised by myopathy and encephalopathy caused by structurally or functionally impaired mitochondria. The biochemical hallmark of this group of disorders is impaired mitochondrial energy production: Kreb's cycle, respiratory chain, oxidative phosphorylation and beta-oxidation of fatty acids. The presence of lactic acidosis and ragged red fibres, i.e. subsarcolemmal accumulations of abnormally sized mitochondria are highly indicative findings for mitochondrial disease. Classification and diagnostic criteria are based on biochemical findings with a search for specific enzyme deficit and molecular genetic information. Molecular genetic studies aim to identify the mitochondrial DNA changes responsible for the enzyme defect. Ragged red fibres are not essential for diagnosis as they are not present in some diseases. In rare cases, mitochondrial diseases are caused by nuclear DNA defects or, more commonly a mitochondrial DNA deficit. Diagnosis may prove difficult given the pathogenetic complexity and clinical and phenotypical variability of these conditions. Despite indirect symptoms of mitochondrial disease, the enzyme defect and genetic alteration cannot be identified in some cases. The mitochondrial encephalopathies can be classified according to the metabolic pathways involved into impaired transport ot uptake of energy, impaired Kreb's cycle or respiratory chain complexes or complex defects due to mitochondrial DNA changes.

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Perinatal maturation of rat kidney mitochondria

Biochemical Journal ◽

10.1042/bj3050675 ◽

1995 ◽

Vol 305 (2) ◽

pp. 675-680 ◽

Cited By ~ 12

Author(s):

B Prieur ◽

L Cordeau-Lossouarn ◽

A Rotig ◽

J Bismuth ◽

J P Geloso ◽

...

Keyword(s):

Respiratory Chain ◽

Atp Synthase ◽

Nuclear Dna ◽

Citrate Synthase ◽

De Novo ◽

Adenine Nucleotide ◽

Rat Kidney ◽

Oxidative Capacity ◽

Respiratory Chain Complexes ◽

Kidney Mitochondria

In the rat kidney, NaK-ATPase activity increased between days 19 and 20 of gestation (+50%) and between 1 and 24 h after birth (+20%), requiring an increased energy supply. In order to determine whether mitochondrial changes were involved, renal mitochondrial development was investigated from day 19 of gestation to 1 day after birth. Slot-blot analyses of mitochondrial-DNA/nuclear-DNA ratio and determination of citrate synthase activity showed a doubling in the mitochondrial pool between days 19 and 20 of gestation. In isolated mitochondria, oxygen consumption remained unchanged between days 19 and 20 of gestation, and then it was enhanced between days 20 and 21 of gestation (+70%) and between 1 and 24 h after birth (+50%). We also focused on one of the respiratory-chain complexes, ATP synthase, and measured its activity and content during the perinatal period. We demonstrated increases in both activity and content of ATP synthase between days 20 and 21 of gestation and between 1 and 24 h after birth, thus suggesting that changes in ATP synthase activity are ascribed to an increase in the mitochondrial density of ATP synthase complexes. Moreover, the mitochondrial ATP/ADP ratio only increased between 1 and 24 h (+90%), indicating a critical step in the renal respiratory-chain maturation at that time. We therefore conclude that the postnatal enhancement of renal mitochondrial oxidative capacity might depend on protein synthesis de novo and on changes in the adenine nucleotide concentrations.

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Response to “Germ Line Therapy to Cure Mitochondrial Disease: Protocol and Ethics of In Vitro Ovum Nuclear Transplantation” by Donald S. Rubenstein, David C. Thomasma, Eric A. Schon, and Michael J. Zinaman (CQ Vol 4, No 3)

Cambridge Quarterly of Healthcare Ethics ◽

10.1017/s096318019900314x ◽

1999 ◽

Vol 8 (3) ◽

pp. 369-374 ◽

Cited By ~ 2

Author(s):

Imre Szebik

Keyword(s):

Mitochondrial Dna ◽

Mitochondrial Disease ◽

Nuclear Dna ◽

Germ Line ◽

Human Cells ◽

Nuclear Transplantation ◽

Line Therapy ◽

The Social ◽

Safety Considerations

Technical, ethical, and social questions of germ-line gene interventions have been widely discussed in the literature. The majority of these discussions focus on planned interventions executed on the nuclear DNA (nDNA). However, human cells also contain another set of genes that is the mitochondrial DNA (mtDNA). As the characteristics of the mtDNA grossly differ from those of nDNA, so do the social, ethical, psychological, and safety considerations of possible interventions on this part of the genetic substance.

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Mitochondrial Diseases: Therapeutic Approaches

Bioscience Reports ◽

10.1007/s10540-007-9041-4 ◽

2007 ◽

Vol 27 (1-3) ◽

pp. 125-137 ◽

Cited By ~ 81

Author(s):

Salvatore DiMauro ◽

Michelangelo Mancuso

Keyword(s):

Respiratory Chain ◽

Nuclear Dna ◽

Palliative Therapy ◽

Real Life ◽

Mitochondrial Diseases ◽

Mitochondrial Respiratory Chain ◽

Preventive Therapy ◽

Therapeutic Approaches ◽

Mitochondrial Encephalomyopathies ◽

Mtdna Mutations

Therapy of mitochondrial encephalomyopathies (defined restrictively as defects of the mitochondrial respiratory chain) is woefully inadequate, despite great progress in our understanding of the molecular bases of these disorders. In this review, we consider sequentially several different therapeutic approaches. Palliative therapy is dictated by good medical practice and includes anticonvulsant medication, control of endocrine dysfunction, and surgical procedures. Removal of noxious metabolites is centered on combating lactic acidosis, but extends to other metabolites. Attempts to bypass blocks in the respiratory chain by administration of electron acceptors have not been successful, but this may be amenable to genetic engineering. Administration of metabolites and cofactors is the mainstay of real-life therapy and is especially important in disorders due to primary deficiencies of specific compounds, such as carnitine or coenzyme Q10. There is increasing interest in the administration of reactive oxygen species scavengers both in primary mitochondrial diseases and in neurodegenerative diseases directly or indirectly related to mitochondrial dysfunction. Aerobic exercise and physical therapy prevent or correct deconditioning and improve exercise tolerance in patients with mitochondrial myopathies due to mitochondrial DNA (mtDNA) mutations. Gene therapy is a challenge because of polyplasmy and heteroplasmy, but interesting experimental approaches are being pursued and include, for example, decreasing the ratio of mutant to wild-type mitochondrial genomes (gene shifting), converting mutated mtDNA genes into normal nuclear DNA genes (allotopic expression), importing cognate genes from other species, or correcting mtDNA mutations with specific restriction endonucleases. Germline therapy raises ethical problems but is being considered for prevention of maternal transmission of mtDNA mutations. Preventive therapy through genetic counseling and prenatal diagnosis is becoming increasingly important for nuclear DNA-related disorders. Progress in each of these approaches provides some glimmer of hope for the future, although much work remains to be done.

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Respiratory-deficient human fibroblasts exhibiting defective mitochondrial DNA replication

Biochemical Journal ◽

10.1042/bj3050817 ◽

1995 ◽

Vol 305 (3) ◽

pp. 817-822 ◽

Cited By ~ 25

Author(s):

A G Bodnar ◽

J M Cooper ◽

J V Leonard ◽

A H V Schapira

Keyword(s):

Mitochondrial Dna ◽

Respiratory Chain ◽

Cultured Cells ◽

Human Fibroblasts ◽

Genetic Defect ◽

Mitochondrial Protein ◽

Mitochondrial Respiratory Chain ◽

Human Cell Line ◽

Respiratory Chain Complexes ◽

Respiratory Deficient

We have characterized cultured skin fibroblasts from two siblings affected with a fatal mitochondrial disease caused by a nuclear genetic defect. Mitochondrial respiratory-chain function was severely decreased in these cells. Southern-blot analysis showed that the fibroblasts had reduced levels of mitochondrial DNA (mtDNA). The mtDNA was unstable and was eliminated from the cultured cells over many generations, generating the rho0 genotype. As the mtDNA level decreased, the cells became more dependent upon pyruvate and uridine for growth. Nuclear-encoded subunits of respiratory-chain complexes were synthesized and imported into the mitochondria of the mtDNA-depleted cells, albeit at reduced levels compared with the controls. Mitochondrial protein synthesis directed by the residual mtDNA indicated that the mtDNA was expressed and that the defect specifically involves the replication or maintenance of mtDNA. This is a unique example of a respiratory-deficient human cell line exhibiting defective mtDNA replication.

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Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase–deficient renal cancer

Science Signaling ◽

10.1126/scisignal.abc4436 ◽

2021 ◽

Vol 14 (664) ◽

pp. eabc4436

Author(s):

Daniel R. Crooks ◽

Nunziata Maio ◽

Martin Lang ◽

Christopher J. Ricketts ◽

Cathy D. Vocke ◽

...

Keyword(s):

Mitochondrial Dna ◽

Respiratory Chain ◽

Human Cancer ◽

Aerobic Glycolysis ◽

Krebs Cycle ◽

Fumarate Hydratase ◽

Mitochondrial Respiratory Chain ◽

Respiratory Chain Complexes ◽

Cycle Enzyme ◽

Mtdna Mutations

Understanding the mechanisms of the Warburg shift to aerobic glycolysis is critical to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by biallelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed impairment of the mitochondrial respiratory chain in tumors from patients with HLRCC. Biochemical and transcriptomic analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)–encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.

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Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect in human adrenocortical cells

Endocrine Related Cancer ◽

10.1530/erc-12-0368 ◽

2013 ◽

Vol 20 (3) ◽

pp. 371-381 ◽

Cited By ~ 50

Author(s):

Ségolène Hescot ◽

Abdelhamid Slama ◽

Anne Lombès ◽

Angelo Paci ◽

Hervé Remy ◽

...

Keyword(s):

Respiratory Chain ◽

Nuclear Dna ◽

Maximum Velocity ◽

Chain Complex ◽

Mitochondrial Respiratory Chain ◽

Dependent Manner ◽

Respiratory Chain Complexes ◽

Adrenocortical Cells ◽

Native Page ◽

Respiratory Chain Defect

Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane is the most effective medical therapy for adrenocortical carcinoma, but its molecular mechanism of action remains poorly understood. Although mitotane is known to have mitochondrial (mt) effects, a direct link to mt dysfunction has never been established. We examined the functional consequences of mitotane exposure on proliferation, steroidogenesis, and mt respiratory chain, biogenesis and morphology, in two human adrenocortical cell lines, the steroid-secreting H295R line and the non-secreting SW13 line. Mitotane inhibited cell proliferation in a dose- and a time-dependent manner. At the concentration of 50 μM (14 mg/l), which corresponds to the threshold for therapeutic efficacy, mitotane drastically reduced cortisol and 17-hydroxyprogesterone secretions by 70%. This was accompanied by significant decreases in the expression of genes encoding mt proteins involved in steroidogenesis (STAR, CYP11B1, and CYP11B2). In both H295R and SW13 cells, 50 μM mitotane significantly inhibited (50%) the maximum velocity of the activity of the respiratory chain complex IV (cytochrome c oxidase (COX)). This effect was associated with a drastic reduction in steady-state levels of the whole COX complex as revealed by blue native PAGE and reduced mRNA expression of both mtDNA-encoded COX2 (MT-CO2) and nuclear DNA-encoded COX4 (COX4I1) subunits. In contrast, the activity and expression of respiratory chain complexes II and III were unaffected by mitotane treatment. Lastly, mitotane exposure enhanced mt biogenesis (increase in mtDNA content and PGC1α (PPARGC1A) expression) and triggered fragmentation of the mt network. Altogether, our results provide first evidence that mitotane induced a mt respiratory chain defect in human adrenocortical cells.

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Leigh Syndrome in a Pedigree Harboring the m.1555A>G Mutation in the Mitochondrial 12S rRNA

Genes ◽

10.3390/genes11091007 ◽

2020 ◽

Vol 11 (9) ◽

pp. 1007

Author(s):

Mouna Habbane ◽

Laura Llobet ◽

M. Pilar Bayona-Bafaluy ◽

José E. Bárcena ◽

Leticia Ceberio ◽

...

Keyword(s):

Hearing Loss ◽

Mitochondrial Dna ◽

Clinical Study ◽

Genetic Disease ◽

Nuclear Dna ◽

Molecular Genetic ◽

Leigh Syndrome ◽

12S Rrna ◽

Mitochondrial 12S Rrna ◽

Cybrid Cell

Background: Leigh syndrome (LS) is a serious genetic disease that can be caused by mutations in dozens of different genes. Methods: Clinical study of a deafness pedigree in which some members developed LS. Cellular, biochemical and molecular genetic analyses of patients’ tissues and cybrid cell lines were performed. Results: mitochondrial DNA (mtDNA) m.1555A>G/MT-RNR1 and m.9541T>C/MT-CO3 mutations were found. The first one is a well-known pathologic mutation. However, the second one does not appear to contribute to the high hearing loss penetrance and LS phenotype observed in this family. Conclusion: The m.1555A>G pathological mutation, accompanied with an unknown nuclear DNA (nDNA) factor, could be the cause of the phenotypic manifestations in this pedigree.

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Endocrine Disorders in Primary Mitochondrial Disease

Journal of the Endocrine Society ◽

10.1210/js.2017-00434 ◽

2018 ◽

Vol 2 (4) ◽

pp. 361-373 ◽

Cited By ~ 18

Author(s):

Iman S Al-Gadi ◽

Richard H Haas ◽

Marni J Falk ◽

Amy Goldstein ◽

Shana E McCormack

Keyword(s):

Mitochondrial Disease ◽

Nuclear Dna ◽

Molecular Genetic ◽

Point Mutations ◽

High Risk Population ◽

Endocrine Disorders ◽

Screening Practices ◽

Abnormal Growth ◽

The North ◽

Adult Participants

Abstract Context Endocrine disorders are common in individuals with mitochondrial disease. To develop evidence-based screening practices in this high-risk population, updated age-stratified estimates of the prevalence of endocrine conditions are needed. Objective To measure the point prevalence of selected endocrine disorders in individuals with mitochondrial disease. Design, Setting, and Patients The North American Mitochondrial Disease Consortium Patient Registry is a large, prospective, physician-curated cohort study of individuals with mitochondrial disease. Participants (n = 404) are of any age, with a diagnosis of primary mitochondrial disease confirmed by molecular genetic testing. Main Outcome Measures Age-specific prevalence of diabetes mellitus (DM), abnormal growth and sexual maturation (AGSM), hypoparathyroidism, and hypothyroidism. Results The majority of our sample was pediatric (<18 years; 60.1%), female (56.9%), and white (85.9%). DM affected 2% of participants aged <18 years [95% confidence interval (CI): 0.4% to 5.7%] and 24.4% of adult participants (95% CI: 18.6% to 30.9%). DM prevalence was highest in individuals with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes syndrome (MELAS; 31.9%, of whom 86.2% had the m.3243A>G mutation). DM occurred more often with mitochondrial DNA defects (point mutations and/or deletions) than with nuclear DNA mutations (23.3% vs 3.7%, respectively; P < 0.001). Other prevalence estimates were 44.1% (95% CI: 38.8% to 49.6%) for AGSM; 0.3% (95% CI: 0% to 1.6%) for hypoparathyroidism; and 6.3% (95% CI: 4% to 9.3%) for hypothyroidism. Conclusion DM and AGSM are highly prevalent in primary mitochondrial disease. Certain clinical mitochondrial syndromes (MELAS and Kearns-Sayre/Pearson syndrome spectrum disorders) demonstrated a higher burden of endocrinopathies. Clinical screening practices should reflect the substantial prevalence of endocrine disorders in mitochondrial disease.

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