212 research outputs found
Leigh syndrome associated with a mutation in the NDUFS7 (PSST) nuclear encoded subunit of complex I
The p.M292T NDUFS2 mutation causes complex I-deficient Leigh syndrome in multiple families
Isolated complex I deficiency is the most frequently observed oxidative phosphorylation defect in children with mitochondrial disease, leading to a diverse range of clinical presentations, including Leigh syndrome. For most patients the genetic cause of the biochemical defect remains unknown due to incomplete understanding of the complex I assembly process. Nonetheless, a plethora of pathogenic mutations have been described to date in the seven mitochondrial-encoded subunits of complex I as well as in 12 of the nuclear-encoded subunits and in six assembly factors. Whilst several mitochondrial DNA mutations are recurrent, the majority of these mutations are reported in single families. We have sequenced core structural and functional nuclear-encoded subunits of complex I in a cohort of 34 paediatric patients with isolated complex I deficiency, identifying pathogenic mutations in 6 patients. These included a novel homozygous NDUFS1 mutation in an Asian child with Leigh syndrome, a previously identified NDUFS8 mutation (c.236C>T, p.P79L) in a second Asian child with Leigh-like syndrome and six novel, compound heterozygous NDUFS2 mutations in four white Caucasian patients with Leigh or Leigh-like syndrome. Three of these children harboured an identical NDUFS2 mutation (c.875T>C, p.M292T), which was also identified in conjunction with a novel NDUFS2 splice site mutation (c.866+4A>G) in a fourth Caucasian child who presented to a different diagnostic centre, with microsatellite and single nucleotide polymorphism analyses indicating that this was due to an ancient common founder event. Our results confirm that NDUFS2 is a mutational hotspot in Caucasian children with isolated complex I deficiency and recommend the routine diagnostic investigation of this gene in patients with Leigh or Leigh-like phenotypes
Multimodal Learning in Health Sciences and Medicine: Merging Technologies to Enhance Student Learning and Communication
Subcomplex Iλ Specifically Controls Integrated Mitochondrial Functions in Caenorhabditis elegans
Complex I dysfunction is a common, heterogeneous cause of human mitochondrial disease having poorly understood pathogenesis. The extensive conservation of complex I composition between humans and Caenorhabditis elegans permits analysis of individual subunit contribution to mitochondrial functions at both the whole animal and mitochondrial levels. We provide the first experimentally-verified compilation of complex I composition in C. elegans, demonstrating 84% conservation with human complex I. Individual subunit contribution to mitochondrial respiratory capacity, holocomplex I assembly, and animal anesthetic behavior was studied in C. elegans by RNA interference-generated knockdown of nuclear genes encoding 28 complex I structural subunits and 2 assembly factors. Not all complex I subunits directly impact respiratory capacity. Subcomplex Iλ subunits along the electron transfer pathway specifically control whole animal anesthetic sensitivity and complex II upregulation, proportionate to their relative impairment of complex I-dependent oxidative capacity. Translational analysis of complex I dysfunction facilitates mechanistic understanding of individual gene contribution to mitochondrial disease. We demonstrate that functional consequences of complex I deficiency vary with the particular subunit that is defective
Reconstructing the evolution of the mitochondrial ribosomal proteome
For production of proteins that are encoded by the mitochondrial genome, mitochondria rely on their own mitochondrial translation system, with the mitoribosome as its central component. Using extensive homology searches, we have reconstructed the evolutionary history of the mitoribosomal proteome that is encoded by a diverse subset of eukaryotic genomes, revealing an ancestral ribosome of alpha-proteobacterial descent that more than doubled its protein content in most eukaryotic lineages. We observe large variations in the protein content of mitoribosomes between different eukaryotes, with mammalian mitoribosomes sharing only 74 and 43% of its proteins with yeast and Leishmania mitoribosomes, respectively. We detected many previously unidentified mitochondrial ribosomal proteins (MRPs) and found that several have increased in size compared to their bacterial ancestral counterparts by addition of functional domains. Several new MRPs have originated via duplication of existing MRPs as well as by recruitment from outside of the mitoribosomal proteome. Using sensitive profile–profile homology searches, we found hitherto undetected homology between bacterial and eukaryotic ribosomal proteins, as well as between fungal and mammalian ribosomal proteins, detecting two novel human MRPs. These newly detected MRPs constitute, along with evolutionary conserved MRPs, excellent new screening targets for human patients with unresolved mitochondrial oxidative phosphorylation disorders
Development of machine learning models to predict posterior capsule rupture based on the EUREQUO registry
Purpose: To evaluate the performance of different probabilistic classifiers to predict posterior capsule rupture (PCR) prior to cataract surgery. Methods: Three probabilistic classifiers were constructed to estimate the probability of PCR: a Bayesian network (BN), logistic regression (LR) model, and multi‐layer perceptron (MLP) network. The classifiers were trained on a sample of 2 853 376 surgeries reported to the European Registry of Quality Outcomes for Cataract and Refractive Surgery (EUREQUO) between 2008 and 2018. The performance of the classifiers was evaluated based on the area under the precision‐recall curve (AUPRC) and compared to existing scoring models in the literature. Furthermore, direct risk factors for PCR were identified by analysing the independence structure of the BN. Results: The MLP network predicted PCR overall the best (AUPRC 13.1 ± 0.41%), followed by the BN (AUPRC 8.05 ± 0.39%) and the LR model (AUPRC 7.31 ± 0.15%). Direct risk factors for PCR include preoperative best‐corrected visual acuity (BCVA), year of surgery, operation type, anaesthesia, target refraction, other ocular comorbidities, white cataract, and corneal opacities. Conclusions: Our results suggest that the MLP network performs better than existing scoring models in the literature, despite a relatively low precision at high recall. Consequently, implementing the MLP network in clinical practice can potentially decrease the PCR rate
A Drosophila model of mitochondrial disease caused by a complex I mutation that uncouples proton pumping from electron transfer
Gene Expression in a Drosophila Model of Mitochondrial Disease
Background
A point mutation in the Drosophila gene technical knockout (tko), encoding mitoribosomal protein S12, was previously shown to cause a phenotype of respiratory chain deficiency, developmental delay, and neurological abnormalities similar to those presented in many human mitochondrial disorders, as well as defective courtship behavior.
Methodology/Principal Findings
Here, we describe a transcriptome-wide analysis of gene expression in tko25t mutant flies that revealed systematic and compensatory changes in the expression of genes connected with metabolism, including up-regulation of lactate dehydrogenase and of many genes involved in the catabolism of fats and proteins, and various anaplerotic pathways. Gut-specific enzymes involved in the primary mobilization of dietary fats and proteins, as well as a number of transport functions, were also strongly up-regulated, consistent with the idea that oxidative phosphorylation OXPHOS dysfunction is perceived physiologically as a starvation for particular biomolecules. In addition, many stress-response genes were induced. Other changes may reflect a signature of developmental delay, notably a down-regulation of genes connected with reproduction, including gametogenesis, as well as courtship behavior in males; logically this represents a programmed response to a mitochondrially generated starvation signal. The underlying signalling pathway, if conserved, could influence many physiological processes in response to nutritional stress, although any such pathway involved remains unidentified.
Conclusions/Significance
These studies indicate that general and organ-specific metabolism is transformed in response to mitochondrial dysfunction, including digestive and absorptive functions, and give important clues as to how novel therapeutic strategies for mitochondrial disorders might be developed.Public Library of Scienc
Mitochondria and Energetic Depression in Cell Pathophysiology
Mitochondrial dysfunction is a hallmark of almost all diseases. Acquired or inherited mutations of the mitochondrial genome DNA may give rise to mitochondrial diseases. Another class of disorders, in which mitochondrial impairments are initiated by extramitochondrial factors, includes neurodegenerative diseases and syndromes resulting from typical pathological processes, such as hypoxia/ischemia, inflammation, intoxications, and carcinogenesis. Both classes of diseases lead to cellular energetic depression (CED), which is characterized by decreased cytosolic phosphorylation potential that suppresses the cell’s ability to do work and control the intracellular Ca2+ homeostasis and its redox state. If progressing, CED leads to cell death, whose type is linked to the functional status of the mitochondria. In the case of limited deterioration, when some amounts of ATP can still be generated due to oxidative phosphorylation (OXPHOS), mitochondria launch the apoptotic cell death program by release of cytochrome c. Following pronounced CED, cytoplasmic ATP levels fall below the thresholds required for processing the ATP-dependent apoptotic cascade and the cell dies from necrosis. Both types of death can be grouped together as a mitochondrial cell death (MCD). However, there exist multiple adaptive reactions aimed at protecting cells against CED. In this context, a metabolic shift characterized by suppression of OXPHOS combined with activation of aerobic glycolysis as the main pathway for ATP synthesis (Warburg effect) is of central importance. Whereas this type of adaptation is sufficiently effective to avoid CED and to control the cellular redox state, thereby ensuring the cell survival, it also favors the avoidance of apoptotic cell death. This scenario may underlie uncontrolled cellular proliferation and growth, eventually resulting in carcinogenesis
Genetics of primary progressive multiple sclerosis
Multiple sclerosis (MS) patients are classified as either having relapsing onset or progressive onset disease, also known as primary progressive MS (PPMS). Relative to relapsing onset patients, PPMS patients are older at disease onset, are equally likely to be men or women, and have more rapid accumulation of disability that does not respond well to treatments used in relapsing onset MS. Although estimates vary, 5-15% of all MS patients have a PPMS disease course. Genetic variance is a proposed determinant of MS disease course. If distinct genes associated with PPMS were identified study of these genes might lead to an understanding of the biology underlying disease progression and neural degeneration that are the hallmarks of PPMS. These genes and their biological pathways might also represent therapeutic targets. This chapter systematically reviews the PPMS genetic literature. Despite the intuitively appealing notion that differences between PPMS and relapsing onset MS are due to genetics, definite differences associated with these phenotypes at the major histocompatibility complex or elsewhere in the genome have not been found. Recent large-scale genome wide screens identified multiple genes associated with MS susceptibility outside the MHC. The genetic variants identified thus far make only weak individual contributions to MS susceptibility. If the genetic effects that contribute to the differences between PPMS and relapsing MS are similar in magnitude to those that distinguish MS from healthy controls then, given the relative scarcity of the PPMS phenotype, very large datasets will be needed to identify PPMS associated genes. International collaborative efforts could provide the means to identify such genes. Alternately, it is possible that factors other than genetics underlie the differences between these clinical phenotypes
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