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1.
Mol Metab ; 66: 101648, 2022 12.
Article in English | MEDLINE | ID: mdl-36455789

ABSTRACT

BACKGROUND: McArdle disease is caused by myophosphorylase deficiency and results in complete inability for muscle glycogen breakdown. A hallmark of this condition is muscle oxidation impairment (e.g., low peak oxygen uptake (VO2peak)), a phenomenon traditionally attributed to reduced glycolytic flux and Krebs cycle anaplerosis. Here we hypothesized an additional role for muscle mitochondrial network alterations associated with massive intracellular glycogen accumulation. METHODS: We analyzed in depth mitochondrial characteristics-content, biogenesis, ultrastructure-and network integrity in skeletal-muscle from McArdle/control mice and two patients. We also determined VO2peak in patients (both sexes, N = 145) and healthy controls (N = 133). RESULTS: Besides corroborating very poor VO2peak values in patients and impairment in muscle glycolytic flux, we found that, in McArdle muscle: (a) damaged fibers are likely those with a higher mitochondrial and glycogen content, which show major disruption of the three main cytoskeleton components-actin microfilaments, microtubules and intermediate filaments-thereby contributing to mitochondrial network disruption in skeletal muscle fibers; (b) there was an altered subcellular localization of mitochondrial fission/fusion proteins and of the sarcoplasmic reticulum protein calsequestrin-with subsequent alteration in mitochondrial dynamics/function; impairment in mitochondrial content/biogenesis; and (c) several OXPHOS-related complex proteins/activities were also affected. CONCLUSIONS: In McArdle disease, severe muscle oxidative capacity impairment could also be explained by a disruption of the mitochondrial network, at least in those fibers with a higher capacity for glycogen accumulation. Our findings might pave the way for future research addressing the potential involvement of mitochondrial network alterations in the pathophysiology of other glycogenoses.


Subject(s)
Glycogen Storage Disease Type V , Male , Female , Mice , Animals , Glycogen Storage Disease Type V/metabolism , Glycogen/metabolism , Muscle, Skeletal/metabolism , Exercise Tolerance , Mitochondria/metabolism
2.
Article in English | MEDLINE | ID: mdl-28674062

ABSTRACT

The antibiotic linezolid is a ribosomal inhibitor with excellent efficacy. Although the administration period has been reduced to 28 days, side effects, usually of hematologic or neuropathic origin, are still reported due to secondary inhibition of mitochondrial protein synthesis. Susceptibility to linezolid toxicity remains unknown. Therefore, the objective of this study was to gain an understanding of clinical heterogeneity in response to identical linezolid exposures through exhaustive examination of the molecular basis of tissue-dependent mitotoxicity, consequent cell dysfunction, and the association of mitochondrial genetics with adverse effects of linezolid administered for the recommended period. Peripheral blood mononuclear cells (PBMC) and skin nerve fibers from 19 and 6 patients, respectively, were evaluated before and after a 28-day linezolid treatment in order to assess toxic effects on mitochondria and cells. Mitochondrial DNA haplotypes and single nucleotide polymorphisms (SNPs) in ribosomal sequences where linezolid binds to mitochondrial ribosomes were also analyzed to investigate their genetic contributions. We found that linezolid reduced mitochondrial protein levels, complex IV activity, and mitochondrial mass in PBMC and was associated with a trend toward an increase in the rate of apoptosis. In skin tissue, mitochondrial mass increased within nerve fibers, accompanied by subclinical axonal swelling. Mitochondrial haplogroup U, mutations in 12S rRNA, and the m.2706A→G, m.3197T→C, and m.3010G→A polymorphisms in 16S rRNA showed a trend toward an association with increased mitochondrial and clinical adverse effects. We conclude that even when linezolid is administered for a shorter time than formerly, adverse effects are reported by 63% of patients. Linezolid exerts tissue-dependent mitotoxicity that is responsible for downstream cellular consequences (blood cell death and nerve fiber swelling), leading to adverse hematologic and peripheral nervous side effects. Multicentric studies should confirm genetic susceptibility in larger cohorts.


Subject(s)
Anti-Bacterial Agents/toxicity , Cyclooxygenase 2/metabolism , Leukocytes, Mononuclear/drug effects , Linezolid/toxicity , Mitochondria/drug effects , Nerve Fibers/drug effects , Protein Synthesis Inhibitors/toxicity , Voltage-Dependent Anion Channels/metabolism , Adult , Aged , Aged, 80 and over , Electron Transport Complex IV/metabolism , Female , Humans , Male , Middle Aged , Mitochondria/genetics , Mitochondrial Proteins/metabolism , Polymorphism, Single Nucleotide/genetics , RNA, Ribosomal/genetics , RNA, Ribosomal, 16S/genetics , Skin/cytology , Skin/innervation
3.
Genes Brain Behav ; 12(8): 812-20, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24118886

ABSTRACT

Mutations in the ATP6 gene are reported to be associated with Leber hereditary optic neuropathy, bilateral striatal necrosis, coronary atherosclerosis risk and neuropathy, ataxia and retinitis pigmentosa (NARP)/maternally inherited Leigh syndromes. Here, we present a patient with NARP syndrome, in whom a previously undescribed mutation was detected in the ATP6 gene: m.8839G>C. Several observations support the concept that m.8839G>C is pathogenically involved in the clinical phenotype of this patient: (1) the mutation was heteroplasmic in muscle; (2) mutation load was higher in the symptomatic patient than in the asymptomatic carriers; (3) cybrids carrying this mutation presented lower cell proliferation, increased mitochondrial DNA (mtDNA) copy number, increased steady-state OxPhos protein levels and decreased mitochondrial membrane potential with respect to isogenic wild-type cybrids; (4) this change was not observed in 2959 human mtDNAs from different mitochondrial haplogroups; (5) the affected amino acid was conserved in all the ATP6 sequences analyzed; and (6) using in silico prediction, the mutation was classified as 'probably damaging'. However, measurement of ATP synthesis showed no differences between wild-type and mutated cybrids. Thus, we suggest that m.8839G>C may lower the efficiency between proton translocation within F0 and F1 rotation, required for ATP synthesis. Further experiments are needed to fully characterize the molecular mechanisms involved in m.8839G>C pathogenicity.


Subject(s)
Mitochondrial Myopathies/genetics , Mitochondrial Proton-Translocating ATPases/genetics , Mutation, Missense , Retinitis Pigmentosa/genetics , Adenosine Triphosphate/biosynthesis , Cell Line, Tumor , Cell Proliferation , DNA, Mitochondrial/genetics , Female , Gene Dosage , Haplotypes , Heterozygote , Humans , Middle Aged , Mitochondrial Myopathies/diagnosis , Mitochondrial Myopathies/metabolism , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Oxidative Phosphorylation , Retinitis Pigmentosa/diagnosis , Retinitis Pigmentosa/metabolism
5.
Clin Nucl Med ; 18(8): 664-7, 1993 Aug.
Article in English | MEDLINE | ID: mdl-8403697

ABSTRACT

Four patients with multiple hepatic cysts were studied: two were diagnosed with Caroli's disease (CD) and two with polycystic hepatic disease (PHD). In CD, hepatic scintigraphy with Tc-99m DISIDA showed areas of focally increased radiotracer accumulation that persisted more than 120 minutes, whereas in PHD, areas of focally decreased radiotracer accumulation were observed with normal liver washout and biliary excretion. When multiple hepatic cysts are shown by abdominal echography or CT scan, hepatic scintigraphy with Tc-99m DISIDA should be performed. This examination is safe and noninvasive, and permits differential diagnosis between CD and PHD.


Subject(s)
Caroli Disease/diagnostic imaging , Cysts/diagnostic imaging , Liver Diseases/diagnostic imaging , Adult , Aged , Diagnosis, Differential , Evaluation Studies as Topic , Female , Humans , Imino Acids , Male , Organotechnetium Compounds , Radionuclide Imaging , Technetium Tc 99m Disofenin
8.
Am J Gastroenterol ; 85(1): 91-3, 1990 Jan.
Article in English | MEDLINE | ID: mdl-2296972

ABSTRACT

Dubin-Johnson syndrome (DJS), a congenital metabolic disorder of bilirubin excretion, was classically diagnosed by the bromsulfalein (BSP) curve and needle hepatic biopsy methods. We present three cases of DJS and propose a new diagnostic approach which could conceivably become a substitute for more aggressive techniques. The results of the 24-h urine coproporphyrin determination and 99mTc-Disofenin scintigraphy gave, together, enough data for an accurate diagnosis.


Subject(s)
Imino Acids , Jaundice, Chronic Idiopathic/diagnosis , Organotechnetium Compounds , Adult , Coproporphyrins/urine , Humans , Jaundice, Chronic Idiopathic/urine , Male , Middle Aged , Technetium Tc 99m Disofenin
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