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Mitochondrion Jun 2024Mitochondrial dysfunction contributes to pathological conditions like ischemia-reperfusion (IR) injury. To address the lack of effective therapeutic interventions for IR... (Review)
Review
Mitochondrial dysfunction contributes to pathological conditions like ischemia-reperfusion (IR) injury. To address the lack of effective therapeutic interventions for IR injury and potential knowledge gaps in the current literature, we systematically reviewed 3800 experimental studies across 5 databases and identified 20 mitochondrial genes impacting IR injury in various organs. Notably, CyPD, Nrf2, and GPX4 are well-studied genes consistently influencing IR injury outcomes. Emerging genes like ALDH2, BNIP3, and OPA1 are supported by human genetic evidence, thereby warranting further investigation. Findings of this review can inform future research directions and inspire therapeutic advancements.
PubMed: 38848983
DOI: 10.1016/j.mito.2024.101908 -
Journal of Cellular and Molecular... Sep 2022Coenzyme Q (CoQ ) is necessary for mitochondrial electron transport. Mutations in CoQ biosynthetic genes cause primary CoQ deficiency (PCoQD) and manifest as... (Review)
Review
Coenzyme Q (CoQ ) is necessary for mitochondrial electron transport. Mutations in CoQ biosynthetic genes cause primary CoQ deficiency (PCoQD) and manifest as mitochondrial disorders. It is often stated that PCoQD patients can be treated by oral CoQ supplementation. To test this, we compiled all studies describing PCoQD patients up to May 2022. We excluded studies with no data on CoQ treatment, or with insufficient description of effectiveness. Out of 303 PCoQD patients identified, we retained 89 cases, of which 24 reported improvements after CoQ treatment (27.0%). In five cases, the patient's condition was reported to deteriorate after halting of CoQ treatment. 12 cases reported improvement in the severity of ataxia and 5 cases in the severity of proteinuria. Only a subjective description of improvement was reported for 4 patients described as responding. All reported responses were partial improvements of only some symptoms. For PCoQD patients, CoQ supplementation is replacement therapy. Yet, there is only very weak evidence for the efficacy of the treatment. Our findings, thus, suggest a need for caution when seeking to justify the widespread use of CoQ for the treatment of any disease or as dietary supplement.
Topics: Ataxia; Humans; Mitochondrial Diseases; Muscle Weakness; Ubiquinone
PubMed: 35985679
DOI: 10.1111/jcmm.17488 -
Kidney International Sep 2022Primary Coenzyme Q10 deficiency is a rare mitochondriopathy with a wide spectrum of organ involvement, including steroid-resistant nephrotic syndrome mainly associated...
Primary Coenzyme Q10 deficiency is a rare mitochondriopathy with a wide spectrum of organ involvement, including steroid-resistant nephrotic syndrome mainly associated with disease-causing variants in the genes COQ2, COQ6 or COQ8B. We performed a systematic literature review, PodoNet, mitoNET, and CCGKDD registries queries and an online survey, collecting comprehensive clinical and genetic data of 251 patients spanning 173 published (47 updated) and 78 new cases. Kidney disease was first diagnosed at median age 1.0, 1.2 and 9.8 years in individuals with disease-causing variants in COQ2, COQ6 and COQ8B, respectively. Isolated kidney involvement at diagnosis occurred in 34% of COQ2, 10.8% of COQ6 and 70.7% of COQ8B variant individuals. Classic infantile multiorgan involvement comprised 22% of the COQ2 variant cohort while 47% of them developed neurological symptoms at median age 2.7 years. The association of steroid-resistant nephrotic syndrome and sensorineural hearing loss was confirmed as the distinctive phenotype of COQ6 variants, with hearing impairment manifesting at average age three years. None of the patients with COQ8B variants, but 50% of patients with COQ2 and COQ6 variants progressed to kidney failure by age five. At adult age, kidney survival was equally poor (20-25%) across all disorders. A number of sequence variants, including putative local founder mutations, had divergent clinical presentations, in terms of onset age, kidney and non-kidney manifestations and kidney survival. Milder kidney phenotype was present in those with biallelic truncating variants within the COQ8B variant cohort. Thus, significant intra- and inter-familial phenotype variability was observed, suggesting both genetic and non-genetic modifiers of disease severity.
Topics: Ataxia; Genetic Association Studies; Humans; Mitochondrial Diseases; Muscle Weakness; Mutation; Nephrotic Syndrome; Steroids; Ubiquinone
PubMed: 35483523
DOI: 10.1016/j.kint.2022.02.040 -
Journal of Neuromuscular Diseases 2021Leigh syndrome (LS) is the most frequent paediatric clinical presentation of mitochondrial disease. The clinical phenotype of LS is highly heterogeneous. Though...
BACKGROUND
Leigh syndrome (LS) is the most frequent paediatric clinical presentation of mitochondrial disease. The clinical phenotype of LS is highly heterogeneous. Though historically the treatment for LS is largely supportive, new treatments are on the horizon. Due to the rarity of LS, large-scale interventional studies are scarce, limiting dissemination of information of therapeutic options to the wider scientific and clinical community.
OBJECTIVE
We conducted a systematic review of pharmacological therapies of LS following the guidelines for FAIR-compliant datasets.
METHODS
We searched for interventional studies within Clincialtrials.gov and European Clinical trials databases. Randomised controlled trials, observational studies, case reports and case series formed part of a wider MEDLINE search.
RESULTS
Of the 1,193 studies initially identified, 157 met our inclusion criteria, of which 104 were carried over into our final analysis. Treatments for LS included very few interventional trials using EPI-743 and cysteamine bitartrate. Wider literature searches identified case series and reports of treatments repleting glutathione stores, reduction of oxidative stress and restoration of oxidative phosphorylation.
CONCLUSIONS
Though interventional randomised controlled trials have begun for LS, the majority of evidence remains in case reports and case series for a number of treatable genes, encoding cofactors or transporter proteins of the mitochondria. Our findings will form part of the international expert-led Solve-RD efforts to assist clinicians initiating treatments in patients with treatable variants of LS.
Topics: Child; Humans; Leigh Disease; Mitochondria; Phenotype
PubMed: 34308912
DOI: 10.3233/JND-210715 -
Genes Feb 2023Defect of , the human mitochondrial tRNA-modifying enzyme, can lead to Combined Oxidative Phosphorylation Deficiency 23 (COXPD23). Up to now, about 20 different variants...
Defect of , the human mitochondrial tRNA-modifying enzyme, can lead to Combined Oxidative Phosphorylation Deficiency 23 (COXPD23). Up to now, about 20 different variants of the gene have been reported; however, genotype-phenotype analysis has rarely been described. Here, we reported a 9-year-old boy with COXPD23 who presented with hyperlactatemia, hypertrophic cardiomyopathy, seizures, feeding difficulties, intellectual disability and motor developmental delay, and abnormal visual development. Biallelic pathogenic variants of the gene were identified in this boy, one novel variant c.1102dupC (p. Arg368Profs*22) inherited from the mother and the other known variant c.689A>C (p. Gln230Pro) inherited from father. We curated 18 COXPD23 patients with variants to investigate the genotype-phenotype correlation. We found that hyperlactatemia and cardiomyopathy were critical clinical features in COXPD23 and the average onset age was 1.7 years (3 months of age for the homozygote). Clinical classification of COXPD23 for the two types, severe and mild, was well described in this study. We observed arrhythmia and congestive heart failure frequently in the severe type with early childhood mortality, while developmental delay was mainly observed in the mild type. The proportion of homozygous variants (71.4%) significantly differed from that of compound heterozygous variants (18.1%) in the severe type. Compared with the variants in gnomAD, the proportion of LOFVs in was higher in COXPD23 patients (48.6% versus 8.9%, < 0.0001 ****), and 31% of them were frameshift variants, showing the LOF mechanism of . Additionally, the variants in patients were significantly enriched in the TrmE-type G domain, indicating that the G domain was crucial for protein function. The TrmE-type G domain contained several significant motifs involved in the binding of guanine nucleotides and Mg, the hydrolysis of GTP, and the regulation of the functional status of GTPases. In conclusion, we reported a mild COXPD23 case with typical -related symptoms, including seizures and abnormal visual development seldom observed previously. Our study provides novel insight into understanding the clinical diagnosis and genetic counseling of patients with COXPD23 by exploring the genetic pathogenesis and genotype-phenotype correlation of COXPD23.
Topics: Child; Child, Preschool; Humans; Infant; Male; GTP-Binding Proteins; Hyperlactatemia; Mitochondrial Diseases; Seizures
PubMed: 36980825
DOI: 10.3390/genes14030552 -
Journal of Medical Genetics Apr 2020Pheochromocytoma and paraganglioma (PPGL) are tumours that arise from chromaffin cells. Some genetic mutations influence PPGL, among which, those in genes encoding... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Pheochromocytoma and paraganglioma (PPGL) are tumours that arise from chromaffin cells. Some genetic mutations influence PPGL, among which, those in genes encoding subunits of succinate dehydrogenase (SDHA, SDHB, SDHC and SDHD) and assembly factor (SDHAF2) are the most relevant. However, the risk of metastasis posed by these mutations is not reported except for SDHB and SDHD mutations. This study aimed to update the metastatic risks, considering prevalence and incidence of each SDHx mutation, which were dealt formerly all together.
METHODS
We searched EMBASE and MEDLINE and selected 27 articles. The patients included in the studies were divided into three groups depending on the presence of PPGL. We checked the heterogeneity between studies and performed a meta-analysis using Hartung-Knapp-Sidik-Jonkman method based on a random effect model.
RESULTS
The highest PPGL prevalence was for SDHB mutation, ranging from 23% to 31%, and for SDHC mutation (23%), followed by that for SDHA mutation (16%). The lowest prevalence was for SDHD mutation, ranging from 6% to 8%. SDHAF2 mutation showed no metastatic events. The PPGL incidence showed a tendency similar to that of its prevalence with the highest risk of metastasis posed by SDHB mutation (12%-41%) and the lowest risk by SDHD mutation (~4%).
CONCLUSION
There was no integrated evidence of how SDHx mutations are related to metastatic PPGL. However, these findings suggest that SDHA, SDHB and SDHC mutations are highly associated and should be tested as indicators of metastasis in patients with PPGL.
Topics: Adrenal Gland Neoplasms; Electron Transport Complex II; Germ-Line Mutation; Heterozygote; Humans; Membrane Proteins; Mitochondrial Proteins; Neoplasm Metastasis; Paraganglioma; Pheochromocytoma; Succinate Dehydrogenase
PubMed: 31649053
DOI: 10.1136/jmedgenet-2019-106324 -
Biochimica Et Biophysica Acta.... Oct 2020Malignant conversion of cancer cells requires efficient mitochondria reprogramming orchestrated by hundreds of genes. The transformation includes increased energy...
Malignant conversion of cancer cells requires efficient mitochondria reprogramming orchestrated by hundreds of genes. The transformation includes increased energy demand, biosynthesis of precursors, and reactive oxygen species needed to accelerate cell growth, proliferation, and survival. Reprogramming involves complex gene alterations that have not been methodically curated. Therefore, we systematically analyzed the literature of cancer-related genes in mitochondria. Through the analysis of >2500 PubMed abstracts and >1600 human genes, we identified 228 genes showing clear roles in cancer. Each gene was classified according to their homeostatic function, together with the pathological transitions that contribute to specific cancer hallmarks. The potential clinical relevance of these hallmarks and genes is discussed by representative examples and validated by detecting differences in gene expression levels across 16 different types of cancer. A compendium, including the gene functions and alterations underpinning cancer progression, can be explored at http://bioinformatica.mty.itesm.mx/MitoCancer.
Topics: Cell Proliferation; Cell Transformation, Neoplastic; Databases, Factual; Humans; Mitochondria; Mitochondrial Proteins; Neoplasms; Reactive Oxygen Species
PubMed: 32473387
DOI: 10.1016/j.bbadis.2020.165846 -
Frontiers in Cellular Neuroscience 2023This analytical review summarizes literature data and our own research on HSP70-dependent mechanisms of neuroprotection and discusses potential pharmacological agents...
This analytical review summarizes literature data and our own research on HSP70-dependent mechanisms of neuroprotection and discusses potential pharmacological agents that can influence HSP70 expression to improve neurological outcomes and effective therapy. The authors formed a systemic concepts of the role of HSP70-dependent mechanisms of endogenous neuroprotection aimed at stopping the formation of mitochondrial dysfunction, activation of apoptosis, desensitization of estrogen receptors, reduction of oxidative and nitrosative stress, prevention of morpho-functional changes in brain cells during cerebral ischemia, and experimentally substantiated new target links for neuroprotection. Heat shock proteins (HSPs) are an evolutionarily integral part of the functioning of all cells acting as intracellular chaperones that support cell proteostasis under normal and various stress conditions (hyperthermia, hypoxia, oxidative stress, radiation, etc.). The greatest curiosity in conditions of ischemic brain damage is the HSP70 protein, as an important component of the endogenous neuroprotection system, which, first of all, performs the function of intracellular chaperones and ensures the processes of folding, holding and transport of synthesized proteins, as well as their degradation, both under normoxic conditions and stress-induced denaturation. A direct neuroprotective effect of HSP70 has been established, which is realized through the regulation the processes of apoptosis and cell necrosis due to a long-term effect on the synthesis of antioxidant enzymes, chaperone activity, and stabilization of active enzymes. An increase in the level of HSP70 leads to the normalization of the glutathione link of the thiol-disulfide system and an increase in the resistance of cells to ischemia. HSP 70 is able to activate and regulate compensatory ATP synthesis pathways during ischemia. It was found that in response to the cerebral ischemia formation, HIF-1a is expressed, which initiates the launch of compensatory mechanisms for energy production. Subsequently, the regulation of these processes switches to HSP70, which "prolongs" the action of HIF-1a, and also independently maintains the expression of mitochondrial NAD-dependent malate dehydrogenase activity, thereby maintaining the activity of the malate-aspartate shuttle mechanism for a long time. During ischemia of organs and tissues, HSP70 performs a protective function, which is realized through increased synthesis of antioxidant enzymes, stabilization of oxidatively damaged macromolecules, and direct anti-apoptotic and mitoprotective action. Such a role of these proteins in cellular reactions during ischemia raises the question of the development of new neuroprotective agents which are able to provide modulation/protection of the genes encoding the synthesis of HSP 70 and HIF-1a proteins. Numerous studies of recent years have noted the important role of HSP70 in the implementation of the mechanisms of metabolic adaptation, neuroplasticity and neuroprotection of brain cells, so the positive modulation of the HSP70 system is a perspective concept of neuroprotection, which can improve the efficiency of the treatment of ischemic-hypoxic brain damage and be the basis for substantiating of the feasibility of using of HSP70 modulators as promising neuroprotectors.
PubMed: 37138769
DOI: 10.3389/fncel.2023.1131683 -
European Neuropsychopharmacology : the... Feb 2022Variation in the expression level and activity of genes involved in drug disposition and action in tissues of pharmacological importance have been increasingly...
Variation in the expression level and activity of genes involved in drug disposition and action in tissues of pharmacological importance have been increasingly investigated in patients treated with psychotropic drugs. Findings are promising, but reliable predictive biomarkers of response have yet to be identified. Here we conducted a PRISMA-compliant systematic search of PubMed, Scopus and PsycInfo up to 12 September 2020 for studies investigating RNA expression levels in cells or biofluids from patients with major depressive disorder, schizophrenia or bipolar disorder characterized for response to psychotropic drugs (antidepressants, antipsychotics or mood stabilizers) or adverse effects. Among 5497 retrieved studies, 123 (63 on antidepressants, 33 on antipsychotics and 27 on mood stabilizers) met inclusion criteria. Studies were either focused on mRNAs (n = 96), microRNAs (n = 19) or long non-coding RNAs (n = 1), with only a minority investigating both mRNAs and microRNAs levels (n = 7). The most replicated results include genes playing a role in inflammation (antidepressants), neurotransmission (antidepressants and antipsychotics) or mitochondrial function (mood stabilizers). Compared to those investigating response to antidepressants, studies focused on antipsychotics or mood stabilizers more often showed lower sample size and lacked replication. Strengths and limitations of available studies are presented and discussed in light of the specific designs, methodology and clinical characterization of included patients for transcriptomic compared to DNA-based studies. Finally, future directions of transcriptomics of psychopharmacological interventions in psychiatric disorders are discussed.
Topics: Anticonvulsants; Antimanic Agents; Antipsychotic Agents; Biomarkers; Depressive Disorder, Major; Humans; Mental Disorders; MicroRNAs
PubMed: 35016057
DOI: 10.1016/j.euroneuro.2021.12.005 -
Frontiers in Neuroscience 2022Neurodegenerative diseases (NDs) are generally considered proteinopathies but whereas this may initiate disease in familial cases, onset in sporadic diseases may...
Neurodegenerative diseases (NDs) are generally considered proteinopathies but whereas this may initiate disease in familial cases, onset in sporadic diseases may originate from a gradually disrupted organellar homeostasis. Herein, endolysosomal abnormalities, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and altered lipid metabolism are commonly observed in early preclinical stages of major NDs, including Parkinson's disease (PD) and Alzheimer's disease (AD). Among the multitude of underlying defective molecular mechanisms that have been suggested in the past decades, dysregulation of inter-organellar communication through the so-called membrane contact sites (MCSs) is becoming increasingly apparent. Although MCSs exist between almost every other type of subcellular organelle, to date, most focus has been put on defective communication between the ER and mitochondria in NDs, given these compartments are critical in neuronal survival. Contributions of other MCSs, notably those with endolysosomes and lipid droplets are emerging, supported as well by genetic studies, identifying genes functionally involved in lysosomal homeostasis. In this review, we summarize the molecular identity of the organelle interactome in yeast and mammalian cells, and critically evaluate the evidence supporting the contribution of disturbed MCSs to the general disrupted inter-organellar homeostasis in NDs, taking PD and AD as major examples.
PubMed: 35801175
DOI: 10.3389/fnins.2022.900338