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Altitude, temperature, circadian rhythms and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Henning Wackerhage, Kenneth A. Dyar, Martin Schönfelder
The exact mechanism of oxygen sensing is incompletely understood; however, the following mechanisms have been proposed by which glomus cells could sense oxygen (5, 6): Metabolites, including ATP, AMP, NADH, reactive-oxygen species, or gases such as CO, NO or H2S may be involved (5, 6). A key oxygen-sensing protein is the protein encoded by the Ndufs2 gene. The Ndufs2 protein is part of the electron transport chain and knockout of this gene in mice abolishes the hyperventilatory response to hypoxia, but not to elevated PCO2 levels (7);Low oxygen sensed by a Ndufs2-related mechanism then inhibits potassium (K+) channels leading to a depolarisation of the glomus cells;Depolarisation opens calcium (Ca2+) channels which increase the Ca2+ concentration inside glomus cells;Increased Ca2+ levels trigger a release of poorly characterised mediators (acetylcholine and ATP are candidates) that can activate innervating nerve fibres and carry the hypoxia message to the ventilation-regulating centres of the brain.
Clinical Manifestation of Mitochondrial Disorders in Childhood
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Leigh syndrome (Leigh, 1951) itself has two different meanings. The first represents the radiological or pathological findings of focal bilaterally symmetrical lesions, especially in the thalamus and brainstem regions. The other broadens this meaning to the clinical unit also known as subacute necrotizing encephalomyelopathy. Genetically, LS is very heterogenous and should be defined in by specific mutation or protein deficit where possible, as some particular may specifically differ in their clinical manifestation (e.g., SURF1 or pyruvate-dehydrogenase complex deficiency). In general, LS may be caused by deficits of respiratory chain complex subunits (complex I, II, IV, and V) and their cofactors (e.g., co-enzyme Q10), mutations in nDNA (e.g., SCO2, SURF1), mtDNA encoded tRNA, or the pyruvate dehydrogenase complex (Loeffen et al., 2000; Finsterer, 2008). Mitochondrial respiratory chain complex I (nicotinamide adenine dinucleotide-ubiquinone oxidoreductase) is the largest enzymatic complex of the mitochondrial respiratory chain. Defects in complex I due to nuclear DNA mutations are one of the most frequent casuses of LS. Various mutations in subunits of complex I encoded by nDNA (NDUFV1, NDUFV2, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, and NDUFS8 were reported (Marin et al., 2013).
Liver Pathology in Mitochondrial Complex I Deficiency from Bi-Allelic Mutations in NDUFS2: A Report of Findings at Autopsy
Published in Fetal and Pediatric Pathology, 2020
Ashlie Rubrecht, William Clapp, Archana Shenoy
A three-month-old ex 35-week preterm male presented with a sudden onset hypotonia, hypothermia and poor feeding. He was admitted to the pediatric intensive care unit with concerns for a metabolic disorder. Laboratory work-up demonstrated lactic acidosis measured at 4.4 mmol/L (Normal: 0.3–1.5 mmol/L). Magnetic resonance imaging of the brain with spectroscopy demonstrated abnormal diffusion restriction throughout the white matter tracts concerning for metabolic disease. With these observations, intravenous thiamine was initiated due to suspicion of mitochondrial disease. However, the patient acutely decompensated with frequent episodes of hypotension and persistent desaturations. Parents elected to continue supportive therapy with no escalation of care. Two weeks after presentation, the infant expired, and an autopsy was performed within 24 h (approximate post mortem interval = 18 h) with tissues snap frozen and saved in glutaraldehyde according to a metabolic autopsy protocol [4]. Routine hematoxylin and eosin stained sections of the liver demonstrated diffuse non-zonal small droplet and microvesicular steatosis with scattered clusters of intensely eosinophilic (oncocytic) hepatocytes (Fig. 1A and B). Electron microscopy demonstrated markedly increased hepatocellular mitochondria with abnormal morphology, including occasional tubular cristae and granular matrix densities (Fig. 1C and D). No megamitochondria were identified. Subsequently, a gene panel ordered premortem identified two heterozygous pathogenic variants in the respiratory chain Complex 1 subunit NDUFS2 gene, c.1237 T > C and c.552delC. Parental testing demonstrated that both parents were heterozygous carriers for one pathogenic variant each, confirming that the variants were present on opposite alleles (in trans) in the deceased infant providing genotype–phenotype correlation.
Mapping the human sperm proteome – novel insights into reproductive research
Published in Expert Review of Proteomics, 2023
Mika Alexia Miyazaki, Raquel Lozano Guilharducci, Paula Intasqui, Ricardo Pimenta Bertolla
Proteome alterations were already seen in obesity, which can explain the damage to male fertility. Using LC-MS/MS, Pini and collaborators [44] found 27 significant differentially expressed proteins. Among the proteins identified by the authors, several were connected to the maintenance of inflammation, gene transcription, protein translation, and mainly oxidative stress, which support findings from previous studies [44,53]. Obesity induces chronic inflammatory diseases, and proteins identified as downregulated, such as Protein SGT1 homolog (SUGT1) and Leukotriene A-4 hydrolase (LTA4H), collaborate with the maintenance of this condition, because these proteins regulate NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasomes and contribute with the increasing of pro-inflammatory factors. Eukaryotic translation initiation factor 3 subunit F (EIF3F) and Casein kinase I isoform gamma-1 (CSNK1G1) were in decreased abundance and are related to the regulation of signaling cascades involved with transcription and translation, indicating a possible implication on spermatogenesis phase [44]. In addition to inflammation, oxidative stress is probably one of the major mechanisms involved in the obesity-associated male infertility. Indeed, dysregulation of oxidative stress-associated proteins, such as NDUSF2 and Protein jagunal homolog 1 (JAGN1) [85], and PDIA3 and ACTRT2 [53,98] has been shown in recent years. NDUFS2 protein levels are higher in case of lipid peroxidation while JAGN1 is seen when oxidative stress affects endoplasmic reticulum [44]. Additionally, PDIA3 and Actin-related protein T2 (ACTRT2) levels were decreased in asthenozoospermic men obesity-associated [53] and subjects submitted to heat stress bath [98]. PDIA3 is suggested to be related to flagellum movement, as well as ACTRT2, a cytoskeletal protein located in the tail midpiece. Therefore, it is assumed that the reduced motility is due to lower levels of these proteins.
The importance of genome sequencing: unraveling SSBP1 variant missed by exome sequencing
Published in Ophthalmic Genetics, 2023
Jae Won Jun, Yuri Seo, Sueng-Han Han, Jinu Han
A 36-year-old man visited our clinic for the evaluation of reduced visual acuity and optic atrophy in both eyes, which had persisted from early childhood. His family history included optic atrophy with autosomal dominant traits and his best-corrected visual acuity was 20/500 in both eyes. He did not identify any Ishihara-colored plates and the dilated fundus examination showed generalized optic atrophy, and optical coherence tomography (OCT) showed diffuse thinning of the retinal nerve fiber layers (Figure 1(a–d)). No neurological signs or symptoms were noted. His 57-year-old mother had reduced visual acuity in early childhood, and her best-corrected visual acuity was also 20/500 in both eyes, with bilateral optic atrophy (Figure 1(e–h)). Wide fundus autofluorescence images showed no retinal degeneration (Figure 1(i–j)). Color vision defects were detected and she also denied any neurological symptoms or hearing impairments. Thus, the patient was diagnosed with DOA, and ES was performed; however, ES did not identify any causative variants in the known DOA genes, including ACO2, AFG3L2, DNM1 L, MFN2, NDUFS2, NR2F1, OPA1, OPA3, SPG7, SSBP1, and WFS1. Furthermore, no copy number variations were identified using the ExomeDepth program. Subsequently, GS was performed to identify the hidden genetic variants, which revealed the presence of a novel heterozygous c.364A>G: p.(Lys122Glu) coding variant of SSBP1. This coding variant was not called or detected in ES because of the relatively poor coverage of SSBP1 exon 6 (Figure 2, coverage of SSBP1 whole transcript: x132.8, coverage of exon 6: x48.3). The variant was absent in gnomAD, KRGDB, and BRAVO. In silico prediction tools supported the deleterious effects of this novel variant on SIFT (0.03), Polyphen 2 (0.860), and CADD (24.7). This variant had a highly conserved nucleotide sequence (PhyloP score 4.40) and was considered likely pathogenic according to the guidelines of the American College of Medical Genetics. Segregation analysis revealed that this novel variant existed in both, the affected mother and 33-year-old clinically unaffected sister (Figure 3a). Multiple alignments of SSBP1 orthologs confirmed the strict conservation of the affected amino acid residues across evolution, except for the fruit fly (Figure 3b). OCT confirmed that no retinal abnormalities, including foveopathy or rod-cone dystrophy, were found in this family.