Mitochondrial mosaics in the liver of 3 infants with mtDNA defects

<p>Abstract</p> <p>Background</p> <p>In muscle cytochrome oxidase (COX) negative fibers (mitochondrial mosaics) have often been visualized.</p> <p>Methods</p> <p>COX activity staining of liver for light and electron microscopy, muscle stains, blue native gel electrophoresis and activity assays of respiratory chain proteins, their immunolocalisation, mitochondrial and nuclear DNA analysis.</p> <p>Results</p> <p>Three unrelated infants showed a mitochondrial mosaic in the liver after staining for COX activity, i.e. hepatocytes with strongly reactive mitochondria were found adjacent to cells with many negative, or barely reactive, mitochondria. Deficiency was most severe in the patient diagnosed with Pearson syndrome. Ragged-red fibers were absent in muscle biopsies of all patients. Enzyme biochemistry was not diagnostic in muscle, fibroblasts and lymphocytes. Blue native gel electrophoresis of liver tissue, but not of muscle, demonstrated a decreased activity of complex IV; in both muscle and liver subcomplexes of complex V were seen. Immunocytochemistry of complex IV confirmed the mosaic pattern in two livers, but not in fibroblasts. MRI of the brain revealed severe white matter cavitation in the Pearson case, but only slight cortical atrophy in the Alpers-Huttenlocher patient, and a normal image in the 3rd. MtDNA in leucocytes showed a common deletion in 50% of the mtDNA molecules of the Pearson patient. In the patient diagnosed with Alpers-Huttenlocher syndrome, mtDNA was depleted for 60% in muscle. In the 3rd patient muscular and hepatic mtDNA was depleted for more than 70%. Mutations in the nuclear encoded gene of <it>POLG </it>were subsequently found in both the 2nd and 3rd patients.</p> <p>Conclusion</p> <p>Histoenzymatic COX staining of a liver biopsy is fast and yields crucial data about the pathogenesis; it indicates whether mtDNA should be assayed. Each time a mitochondrial disorder is suspected and muscle data are non-diagnostic, a liver biopsy should be recommended. Mosaics are probably more frequent than observed until now. A novel pathogenic mutation in <it>POLG </it>is reported.</p> <p>Tentative explanations for the mitochondrial mosaics are, in one patient, unequal partition of mutated mitochondria during mitoses, and in two others, an interaction between products of several genes required for mtDNA maintenance.</p

MtDNA-maintenance defects: syndromes and genes

A large group of mitochondrial disorders, ranging from early-onset pediatric encephalopathic syndromes to late-onset myopathy with chronic progressive external ophthalmoplegia (CPEOs), are inherited as Mendelian disorders characterized by disturbed mitochondrial DNA (mtDNA) maintenance. These errors of nuclear-mitochondrial intergenomic signaling may lead to mtDNA depletion, accumulation of mtDNA multiple deletions, or both, in critical tissues. The genes involved encode proteins belonging to at least three pathways: mtDNA replication and maintenance, nucleotide supply and balance, and mitochondrial dynamics and quality control. In most cases, allelic mutations in these genes may lead to profoundly different phenotypes associated with either mtDNA depletion or multiple deletions. Communicated by: Shamima Rahman Presented at the Annual Symposium of the Society for the Study of Inborn Errors of Metabolism, Rome, Italy, September 6–9, 2016This work was supported by: ERC FP7-322424 grant (to MZ), CoEN grant 3038 (to MZ and CV) and the MRC core grant to the Mitochondrial Biology Unit

The peroxisome: still a mysterious organelle

More than half a century of research on peroxisomes has revealed unique features of this ubiquitous subcellular organelle, which have often been in disagreement with existing dogmas in cell biology. About 50 peroxisomal enzymes have so far been identified, which contribute to several crucial metabolic processes such as β-oxidation of fatty acids, biosynthesis of ether phospholipids and metabolism of reactive oxygen species, and render peroxisomes indispensable for human health and development. It became obvious that peroxisomes are highly dynamic organelles that rapidly assemble, multiply and degrade in response to metabolic needs. However, many aspects of peroxisome biology are still mysterious. This review addresses recent exciting discoveries on the biogenesis, formation and degradation of peroxisomes, on peroxisomal dynamics and division, as well as on the interaction and cross talk of peroxisomes with other subcellular compartments. Furthermore, recent advances on the role of peroxisomes in medicine and in the identification of novel peroxisomal proteins are discussed

Response of circulating adrenocorticotropin, beta-endorphin, beta-lipotropin and cortisol to athletic competition.

Acute physical exercise stimulates the activity of the hypothalamus-pituitary-adrenal axis in man. In the present study we measured plasma adrenocorticotropin, beta-endorphin, beta-lipotropin and cortisol levels in 27 male trained athletes in basal conditions, 60 min before and immediately after an official competition. The endocrine responses were evaluated in different groups of athletes participating in races (100 m, 1500 m, 10,000 m) or in the disc throw. The athletes competing for the runs showed a statistically significant increase in plasma adrenocorticotropin, beta-endorphin, beta-lipotropin and cortisol levels after the race (P less than 0.01), whereas the disc throwers showed no significant change in the hypothalamus-pituitary-adrenal axis hormones after the competition. The percent increase in plasma adrenocorticotropin, beta-endorphin, beta-lipotropin and cortisol was higher in the athletes who run 1500 m and 10,000 m than in those participating in the short distance race (100 m). The present results showed that plasma proopiomelanocortin-related peptides and cortisol levels increase in trained athletes following running competition and that this increase is related to the duration of the physical exercise

Response of circulating adrenocorticotropin, beta-endorphin, beta-lipotropin and cortisol to athletic competition.

Acute physical exercise stimulates the activity of the hypothalamus-pituitary-adrenal axis in man. In the present study we measured plasma adrenocorticotropin, beta-endorphin, beta-lipotropin and cortisol levels in 27 male trained athletes in basal conditions, 60 min before and immediately after an official competition. The endocrine responses were evaluated in different groups of athletes participating in races (100 m, 1500 m, 10,000 m) or in the disc throw. The athletes competing for the runs showed a statistically significant increase in plasma adrenocorticotropin, beta-endorphin, beta-lipotropin and cortisol levels after the race (P less than 0.01), whereas the disc throwers showed no significant change in the hypothalamus-pituitary-adrenal axis hormones after the competition. The percent increase in plasma adrenocorticotropin, beta-endorphin, beta-lipotropin and cortisol was higher in the athletes who run 1500 m and 10,000 m than in those participating in the short distance race (100 m). The present results showed that plasma proopiomelanocortin-related peptides and cortisol levels increase in trained athletes following running competition and that this increase is related to the duration of the physical exercis