respiratory chain complex disorders

This paper provides an overview of the different types of mitochondrial myopathies (MM), associated phenotypes, genotypes as well as a practical clinical approach towards disease diagnosis, surveillance, and management. nDNA-related MM are more common in pediatric-onset disease whilst mtDNA-related MMs are more frequent in adults. Genotype-phenotype correlation in MM is challenging due to clinical and genetic heterogeneity. The multisystemic nature of many MMs adds to the diagnostic challenge. Diagnostic approaches utilizing genetic sequencing with next generation sequencing approaches such as gene panel, exome and genome sequencing are available...

Kearns-Sayre syndrome (KSS) is a rare multisystem mitochondrial disorder. It is caused by mitochondrial DNA (mtDNA) rearrangements, mostly large-scale deletions of 1.1-10 kb. These deletions primarily affect energy supply through impaired oxidative phosphorylation and reduced ATP production. This impairment gives rise to dysfunction of several tissues, in particular those with high energy demand like brain and muscles. Over the past decades, changes in respiratory chain complexes and energy metabolism have been emphasized, whereas little attention has been paid to other reports on ROS overproduction, protein synthesis inhibition, myelin vacuolation, demyelination, autophagy, apoptosis, and involvement of lipid raft and oligodendrocytes in KSS...

BACKGROUND: The NADH dehydrogenase [ubiquinone] iron-sulfur protein 6 (NDUFS6) gene encodes for an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Bi-allelic NDUFS6 variants have been linked with a severe disorder mostly reported as a lethal infantile mitochondrial disease (LMID) or Leigh syndrome (LS). OBJECTIVE: Here, we identified a homozygous variant (c.309 + 5 G >  A) in NDUFS6 in one male patient with axonal neuropathy accompanied by loss of small fibers in skin biopsy and further complicated by optic atrophy and borderline intellectual disability...

Insulin resistance (IR) is a complex metabolic disorder that underlies several human diseases, including type 2 diabetes and cardiovascular disease. Despite extensive research, the precise mechanisms underlying IR development remain poorly understood. Previously we showed that deficiency of coenzyme Q (CoQ) is necessary and sufficient for IR in adipocytes and skeletal muscle (Fazakerley et al., 2018). Here, we provide new insights into the mechanistic connections between cellular alterations associated with IR, including increased ceramides, CoQ deficiency, mitochondrial dysfunction, and oxidative stress...

BACKGROUND: Dilated cardiomyopathy with ataxia (DCMA) is an autosomal recessive disorder arising from truncating mutations in DNAJC19, which encodes an inner mitochondrial membrane protein. Clinical features include an early onset, often life-threatening, cardiomyopathy associated with other metabolic features. Here, we aim to understand the metabolic and pathophysiological mechanisms of mutant DNAJC19 for the development of cardiomyopathy. METHODS: We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two affected siblings with DCMA and a gene-edited truncation variant (tv) of DNAJC19which all lack the conserved DnaJ interaction domain...

Metformin, a widely prescribed medication for type 2 diabetes, has garnered increasing attention for its potential neuroprotective properties due to the growing demand for treatments for Alzheimer's, Parkinson's, and motor neuron diseases. This review synthesizes experimental and clinical studies on metformin's mechanisms of action and potential therapeutic benefits for neurodegenerative disorders. A comprehensive search of electronic databases, including PubMed, MEDLINE, Embase, and Cochrane library, focused on key phrases such as "metformin", "neuroprotection", and "neurodegenerative diseases", with data up to September 2023...

BACKGROUND: Chronic pain is a common, complex, and challenging condition, for which specialised healthcare is required. We investigated the relationship between multisite chronic pain (MCP) and different disease traits identify safe biomarker interventions that can prevent MCP. METHODS: Univariable and multivariable Mendelian randomisation (MR) analysis were conducted to investigate associations between MCP and 36 common diseases in the UK Biobank. Subsequently, we estimated the potential effect of expression of 4774 proteins on MCP utilising existing plasma protein quantitative trait locus data...

Isolated mitochondrial respiratory chain Complex IV (Cytochrome c Oxidase or COX) deficiency is the second most frequent isolated respiratory chain defect. Causative mutations are mainly identified in structural COX subunits or in proteins involved in the maturation and assembly of the COX holocomplex. We describe an Italian familial case of mitochondrial myopathy due to a variant in the COX assembly factor 8 gene ( COA8 ). Patient 1 is a 52-year-old woman who presented generalized epilepsy and retinitis pigmentosa at 10 years of age...

MRPS23 is a nuclear gene encoding a mitochondrial ribosomal protein. A patient with a mitochondrial disorder was found to carry a variant in MRPS23. More cases are necessary to establish MRPS23 as a mitochondrial disease gene. Of 5134 exomes performed in our center, we identified five independent patients who had similar clinical manifestations and were homozygous for the same germline variant c.119C>T; p.P40L in MRPS23. Detailed clinical findings, mitochondrial enzyme activity assays from cultured skin fibroblasts, PCR-Sanger-sequencing, and variant age estimation were performed...

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A 16-year-old boy was evaluated for a history of exercise-induced fatigability associated with nausea even after minimal effort, lower limbs muscle hypotrophy, and swelling of the masseter muscles after chewing. Laboratory tests were remarkable for hyperlactatemia and metabolic acidosis after short physical activity. The muscle biopsy showed non-specific mitochondrial alterations and an increase in intrafibral lipids. Biochemical analysis showed reduced activity of the respiratory chain complexes. Mitochondrial DNA sequencing revealed the presence of a homoplasmic variant m...

With population aging, cognitive impairments and movement disorders due to neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB), are increasingly considered as key social issues. Clinically, it has remained challenging to diagnose them before the onset of symptoms because of difficulty to observe the progressive loss of neurons in the brain. Therefore, with exploratory research into biomarkers, a number of candidates have previously been proposed, such as activities of mitochondrial respiratory chain complexes in blood in AD and PD...

Neurodegenerative diseases, including Parkinson's Disease (PD), and cellular disturbances such as cancer are some of the disorders that disrupt energy metabolism with impairment of mitochondrial functions. Mitochondria are organelles that control both energy metabolism and cellular processes involved in cell survival and death. For this reason, approaches to evaluate mitochondrial function can offer important insights into cellular conditions in pathological and physiological processes. In this regard, high-resolution respirometry (HRR) protocols allow evaluation of the whole mitochondrial respiratory chain function or the activity of specific mitochondrial complexes...

Aminoacylase 1 (ACY1) deficiency is an inherited metabolic disorder biochemically characterized by high urinary concentrations of aliphatic N-acetylated amino acids and associated with a broad clinical spectrum with predominant neurological signs. Considering that the pathogenesis of ACY1 is practically unknown and the brain is highly dependent on energy production, the in vitro effects of N-acetylglutamate (NAG) and N-acetylmethionine (NAM), major metabolites accumulating in ACY1 deficiency, on the enzyme activities of the citric acid cycle (CAC), of the respiratory chain complexes and glutamate dehydrogenase (GDH), as well as on ATP synthesis were evaluated in brain mitochondrial preparations of developing rats...

INTRODUCTION: Pyruvate Dehydrogenase Complex (PDC) is a pivotal gatekeeper between cytosolic glycolysis and mitochondrial oxidative phosphorylation, playing important role in aerobic energy metabolism. Most PDC deficiency, cases being caused by mutations in PDHA1 encoding the α subunit of the rate-limiting E1 enzyme, which is characterized by abnormal phenotypes caused by energy deprivation at peripheral/central nervous systems and muscular tissues. This study aims to evaluate the potential therapeutic effect of arginine and thiamine in ameliorating mitochondrial function in patient-derived cultured cells...

INTRODUCTION: Leigh syndrome (LS) is clinically and genetically heterogeneous and presents defective mitochondrial bioenergetics. Patients present neurological symptoms and imagiological features that may result in early death [1]. The LS has been associated with mitochondrial DNA (mtDNA) variants, e.g., m.8993T>G (L156R) and m.8993T>C (L156P), in the MT-ATP6 gene. They lead to the substitution of a highly conserved amino acid in subunit 6 of ATP synthase, affecting the F0 domain and ATP synthesis [1-3]...

Pathogenic variants in MFN2 gene are commonly associated with autosomal dominant (CMT2A2A) or recessive (CMT2A2B) Charcot-Marie-Tooth disease, with possible involvement of the central nervous system. Here, we present a case of severe antenatal encephalopathy with lissencephaly, polymicrogyria and cerebellar atrophy. Whole Genome Analysis revealed a homozygous deletion c.1717-274_1734 del (NM_014874.4) in MFN2 gene, leading to exon 16 skipping and in-frame loss of 50 amino acids (p.Gln574_Val624del), removing the proline rich domain and the transmembrane domain 1 (TM1)...

OBJECTION: To investigate the potential link between aberrant mitochondrial energy metabolism mediated by the AMPK/SIRT1 pathway and the etiology of anxiety disorders. METHODS: The anxiety rat model was established by uncertain empty water bottle（UEWB）stress. Rats were submitted behavioral tests on the seventh, fourteenth, and twenty-first days and had the prefrontal cortex and amygdala removed for biochemical tests. The morphological alterations of the mitochondria in the medial prefrontal cortex and amygdala were examined by using a transmission electron microscope...

Diabetes mellitus (DM) is a metabolic disorder characterized by persistent hyperglycemia. This state may lead to an increase in oxidative stress, which contributes to the development of diabetes complications, including diabetic kidney disease. Potentilla indica is a traditional medicinal herb in Asia, employed in the treatment of several diseases, including DM. In this study, we investigated the antioxidant effect of the ethyl acetate extract of Potentilla indica both in vitro and on kidneys of streptozotocin-induced diabetic male rats...

Bisphenol A (BPA), a component of plastic products, can penetrate the blood-brain barrier and pose a threat to the nervous system. Selenium (Se) deficiency can also cause nervous system damage. Resulting from the rapid industrial development, BPA pollution and Se deficiency often coexist. However, it is unclear whether brain damage in chickens caused by BPA exposure and Se deficiency is related to the crosstalk disorder between mitophagy and apoptosis. In this study, 60 chickens (1 day old) were fed with a diet that contained 20 mg/kg BPA but was insufficient in Se (only 0...