bims-symami 2023-04-02 papers

bims-symami

Biomed News

on Symptom management in mitochondrial disease

Issue of 2023–04–02
eleven papers selected by
The Lily Foundation

Mitochondrial transplantation as a promising therapy for mitochondrial diseases.
Mitochondrial Base Editing: Recent Advances towards Therapeutic Opportunities.
Mitochondrial DNA abnormalities and metabolic syndrome.
[Analysis of clinical phenotype and genetic variants in a child with mitochondrial F-S disease due to variants of FDXR gene].
Primary mitochondrial disease as a rare cause of unclear breathlessness and distinctive performance degradation - a case report.
The Role of Primary Mitochondrial Disorders in Hearing Impairment: An Overview.
Gene Therapy for Regenerative Medicine.
Differential Role of Active Compounds in Mitophagy and Related Neurodegenerative Diseases.
Metabolomic Studies in Inborn Errors of Metabolism: Last Years and Future Perspectives.
The P2X7 Receptor as a Mechanistic Biomarker for Epilepsy.
Treatment of neurometabolic epilepsies: Overview and recent advances.

Acta Pharm Sin B. 2023 Mar;13(3): 1028-1035

Mitochondrial transplantation as a promising therapy for mitochondrial diseases.

Tian-Guang Zhang, Chao-Yu Miao.

  Mitochondrial diseases are a group of inherited or acquired metabolic disorders caused by mitochondrial dysfunction which may affect almost all the organs in the body and present at any age. However, no satisfactory therapeutic strategies have been available for mitochondrial diseases so far. Mitochondrial transplantation is a burgeoning approach for treatment of mitochondrial diseases by recovery of dysfunctional mitochondria in defective cells using isolated functional mitochondria. Many models of mitochondrial transplantation in cells, animals, and patients have proved effective via various routes of mitochondrial delivery. This review presents different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application. Despite some unknowns and challenges, mitochondrial transplantation would provide an innovative approach for mitochondrial medicine.

Keywords:  Ethical issue; Mitochondria; Mitochondrial delivery; Mitochondrial disease; Mitochondrial isolation; Mitochondrial storage; Mitochondrial transplantation; Mitochondrial transplantation rejection

DOI:  https://doi.org/10.1016/j.apsb.2022.10.008
Int J Mol Sci. 2023 Mar 18. pii: 5798. [Epub ahead of print]24(6):

Mitochondrial Base Editing: Recent Advances towards Therapeutic Opportunities.

Bibekananda Kar, Santiago R Castillo, Ankit Sabharwal, Karl J Clark, Stephen C Ekker.

  Mitochondria are critical organelles that form networks within our cells, generate energy dynamically, contribute to diverse cell and organ function, and produce a variety of critical signaling molecules, such as cortisol. This intracellular microbiome can differ between cells, tissues, and organs. Mitochondria can change with disease, age, and in response to the environment. Single nucleotide variants in the circular genomes of human mitochondrial DNA are associated with many different life-threatening diseases. Mitochondrial DNA base editing tools have established novel disease models and represent a new possibility toward personalized gene therapies for the treatment of mtDNA-based disorders.

Keywords:  DdCBE; TALED; base editing; heteroplasmy; mitochondria; mitochondrial DNA

DOI:  https://doi.org/10.3390/ijms24065798
Front Cell Dev Biol. 2023 ;11 1153174

Mitochondrial DNA abnormalities and metabolic syndrome.

Xudong Ding, Tingting Fang, Xiaoqi Pang, Xueru Pan, Aiying Tong, Ziyi Lin, Shikuan Zheng, Ningning Zheng.

  Metabolic syndrome (MetS) is a complex pathological condition that involves disrupted carbohydrate, protein, and fat metabolism in the human body, and is a major risk factor for several chronic diseases, including diabetes, cardiovascular disease, and cerebrovascular disease. While the exact pathogenesis of metabolic syndrome is not yet fully understood, there is increasing evidence linking mitochondrial dysfunction, which is closely related to the mitochondrial genome and mitochondrial dynamics, to the development of this condition. Recent advancements in genetic sequencing technologies have allowed for more accurate detection of mtDNA mutations and other mitochondrial abnormalities, leading to earlier diagnosis and intervention in patients with metabolic syndrome. Additionally, the identification of specific mechanisms by which reduced mtDNA copy number and gene mutations, as well as abnormalities in mtDNA-encoded proteins and mitochondrial dynamics, contribute to metabolic syndrome may promote the development of novel therapeutic targets and interventions, such as the restoration of mitochondrial function through the targeting of specific mitochondrial defects. Additionally, advancements in genetic sequencing technologies may allow for more accurate detection of mtDNA mutations and other mitochondrial abnormalities, leading to earlier diagnosis and intervention in patients with MetS. Therefore, strategies to promote the restoration of mitochondrial function by addressing these defects may offer new options for treating MetS. This review provides an overview of the research progress and significance of mitochondrial genome and mitochondrial dynamics in MetS.

Keywords:  metabolic syndrome; mitochondrial copy number; mitochondrial dynamics; mitochondrial gene mutations; mitochondrial proteases; mitochondrial-encoded proteins

DOI:  https://doi.org/10.3389/fcell.2023.1153174
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2023 Apr 10. 40(4): 413-418

[Analysis of clinical phenotype and genetic variants in a child with mitochondrial F-S disease due to variants of FDXR gene].

Wenjing Hu, Xiuxin Ling, Hongjun Fang, Jingwen Tang, Qingyun Kang, Haiyan Yang, Liwen Wu.

OBJECTIVE: To analyze the clinical phenotype and genetic variants of a child suspected for mitochondrial F-S disease.
METHODS: A child with mitochondrial F-S disease who visited Department of Neurology, Hunan Provincial children's Hospital on November 5, 2020 was selected as research subject of this study. Clinical data of the child was collected. The child was subjected to whole exome sequencing (WES). Bioinformatics tools were used to analyze the pathogenic variants. Candidate variants were verified by Sanger sequencing of the child and her parents.
RESULTS: WES revealed that the child has harbored compound heterozygous variants of the FDXR gene, namely c.310C>T (p.R104C) and c.235C>T (p.R79C), which were inherited from her father and mother, respectively. Neither variant has been reported in HGMD, PubMed, 1000 Genomes, and dbSNP databases. Both of the variants have been suggested as deleterious according to the prediction results from different bioinformatics analysis software.
CONCLUSION: Mitochondrial diseases should be suspected for patients with multiple system involvement. The compound heterozygous variants of the FDXR gene probably underlay the disease in this child. Above finding has enriched the spectrum of FDXR gene mutations underlying mitochondrial F-S disease. WES can facilitate the diagnosis of mitochondrial F-S disease at the molecular level.

DOI: https://doi.org/10.3760/cma.j.cn511374-20220520-00341
BMC Pulm Med. 2023 Mar 29. 23(1): 104

Primary mitochondrial disease as a rare cause of unclear breathlessness and distinctive performance degradation - a case report.

Ralf Ewert, Mohamed A Elhadad, Dirk Habedank, Alexander Heine, Beate Stubbe.

   BACKGROUND: Primary muscular disorders (metabolic myopathies, including mitochondrial disorders) are a rare cause of dyspnea. We report a case of dyspnea caused by a mitochondrial disorder with a pattern of clinical findings that can be classified in the known pathologies of mitochondrial deletion syndrome.
CASE PRESENTATION: The patient presented to us at 29 years of age, having had tachycardia, dyspnea, and functional impairment since childhood. She had been diagnosed with bronchial asthma and mild left ventricular hypertrophy and treated accordingly, but her symptoms had worsened. After more than 20 years of progressive physical and social limitations was a mitochondrial disease suspected in the exercise testing. We performed cardiopulmonary exercise testing (CPET) with right heart catheterization showed typical signs of mitochondrial myopathy. Genetic testing confirmed the presence of a ~ 13 kb deletion in mitochondrial DNA from the muscle. The patient was treated with dietary supplements for 1 year. In the course of time, the patient gave birth to a healthy child, which is developing normally.
CONCLUSION: CPET and lung function data over 5 years demonstrated stable disease. We conclude that CPET and lung function analysis should be used consistently to evaluate the cause of dyspnea and for long-term observation.

Keywords:  Case report; Dyspnea; Invasive cardiopulmonary exercise testing; Lactate; Metabolic myopathy; Mitochondriopathy

DOI:  https://doi.org/10.1186/s12890-023-02391-x
Medicina (Kaunas). 2023 Mar 19. pii: 608. [Epub ahead of print]59(3):

The Role of Primary Mitochondrial Disorders in Hearing Impairment: An Overview.

Virginia Fancello, Giuseppe Fancello, Silvia Palma, Daniele Monzani, Elisabetta Genovese, Chiara Bianchini, Andrea Ciorba.

  Background. Defects of mitochondrial DNA (mtDNA) involved in the function of the mitochondrial electron transport chain can result in primary mitochondrial diseases (PMDs). Various features can influence the phenotypes of different PMDs, with relevant consequences on clinical presentation, including the presence of hearing impairment. This paper aims to describe the hearing loss related to different PMDs, and when possible, their phenotype. Methods. A systematic review was performed according to PRISMA guidelines, searching Medline until December 2022. A total of 485 papers were identified, and based on specified criteria, 7 were included in this study. Results. A total of 759 patients affected by PMDs and hearing loss were included. The age of patients ranged from 2 days to 78 years old, and the male-to-female ratio was 1.3:1. The percentage of subjects affected by hearing loss was 40.8%, (310/759), and in most cases, hearing impairment was described as sensorineural, bilateral, symmetrical, and progressive, with different presentations depending on age and syndrome severity. Conclusions. PMDs are challenging conditions with different clinical phenotypes. Hearing loss, especially when bilateral and progressive, may represent a red flag; its association with other systemic disorders (particularly neuromuscular, ocular, and endocrine) should alert clinicians, and confirmation via genetic testing is mandatory nowadays.

Keywords:  genetics; metabolic disorders; mitochondrial diseases; sensorineural hearing loss

DOI:  https://doi.org/10.3390/medicina59030608
Pharmaceutics. 2023 Mar 06. pii: 856. [Epub ahead of print]15(3):

Gene Therapy for Regenerative Medicine.

Hossein Hosseinkhani, Abraham J Domb, Ghorbanali Sharifzadeh, Victoria Nahum.

  The development of biological methods over the past decade has stimulated great interest in the possibility to regenerate human tissues. Advances in stem cell research, gene therapy, and tissue engineering have accelerated the technology in tissue and organ regeneration. However, despite significant progress in this area, there are still several technical issues that must be addressed, especially in the clinical use of gene therapy. The aims of gene therapy include utilising cells to produce a suitable protein, silencing over-producing proteins, and genetically modifying and repairing cell functions that may affect disease conditions. While most current gene therapy clinical trials are based on cell- and viral-mediated approaches, non-viral gene transfection agents are emerging as potentially safe and effective in the treatment of a wide variety of genetic and acquired diseases. Gene therapy based on viral vectors may induce pathogenicity and immunogenicity. Therefore, significant efforts are being invested in non-viral vectors to enhance their efficiency to a level comparable to the viral vector. Non-viral technologies consist of plasmid-based expression systems containing a gene encoding, a therapeutic protein, and synthetic gene delivery systems. One possible approach to enhance non-viral vector ability or to be an alternative to viral vectors would be to use tissue engineering technology for regenerative medicine therapy. This review provides a critical view of gene therapy with a major focus on the development of regenerative medicine technologies to control the in vivo location and function of administered genes.

Keywords:  biodegradable polymers; gene therapy; nanoparticles; non-viral vectors; regenerative medicine; tissue engineering; viral vectors

DOI:  https://doi.org/10.3390/pharmaceutics15030856
Toxins (Basel). 2023 Mar 06. pii: 202. [Epub ahead of print]15(3):

Differential Role of Active Compounds in Mitophagy and Related Neurodegenerative Diseases.

Mark Makarov, Eduard Korkotian.

  Neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease, significantly reduce the quality of life of patients and eventually result in complete maladjustment. Disruption of the synapses leads to a deterioration in the communication of nerve cells and decreased plasticity, which is associated with a loss of cognitive functions and neurodegeneration. Maintaining proper synaptic activity depends on the qualitative composition of mitochondria, because synaptic processes require sufficient energy supply and fine calcium regulation. The maintenance of the qualitative composition of mitochondria occurs due to mitophagy. The regulation of mitophagy is usually based on several internal mechanisms, as well as on signals and substances coming from outside the cell. These substances may directly or indirectly enhance or weaken mitophagy. In this review, we have considered the role of some compounds in process of mitophagy and neurodegeneration. Some of them have a beneficial effect on the functions of mitochondria and enhance mitophagy, showing promise as novel drugs for the treatment of neurodegenerative pathologies, while others contribute to a decrease in mitophagy.

Keywords:  T-2 toxin; autophagy; haloperidol; mitophagy; neurodegeneration; niclosamide; quercetin; resveratrol; sevoflurane; spermidine; urolithin

DOI:  https://doi.org/10.3390/toxins15030202
Metabolites. 2023 Mar 18. pii: 447. [Epub ahead of print]13(3):

Metabolomic Studies in Inborn Errors of Metabolism: Last Years and Future Perspectives.

Marcello Cossu, Roberta Pintus, Marco Zaffanello, Michele Mussap, Fabiola Serra, Maria Antonietta Marcialis, Vassilios Fanos.

  The inborn errors of metabolism (IEMs or Inherited Metabolic Disorders) are a heterogeneous group of diseases caused by a deficit of some specific metabolic pathways. IEMs may present with multiple overlapping symptoms, sometimes difficult delayed diagnosis and postponed therapies. Additionally, many IEMs are not covered in newborn screening and the diagnostic profiling in the metabolic laboratory is indispensable to reach a correct diagnosis. In recent years, Metabolomics helped to obtain a better understanding of pathogenesis and pathophysiology of IEMs, by validating diagnostic biomarkers, discovering new specific metabolic patterns and new IEMs itself. The expansion of Metabolomics in clinical biochemistry and laboratory medicine has brought these approaches in clinical practice as part of newborn screenings, as an exam for differential diagnosis between IEMs, and evaluation of metabolites in follow up as markers of severity or therapies efficacy. Lastly, several research groups are trying to profile metabolomics data in platforms to have a holistic vision of the metabolic, proteomic and genomic pathways of every single patient. In 2018 this team has made a review of literature to understand the value of Metabolomics in IEMs. Our review offers an update on use and perspectives of metabolomics in IEMs, with an overview of the studies available from 2018 to 2022.

Keywords:  biomarkers; inborn errors of metabolism; metabolomic; newborn screening

DOI:  https://doi.org/10.3390/metabo13030447
Int J Mol Sci. 2023 Mar 12. pii: 5410. [Epub ahead of print]24(6):

The P2X7 Receptor as a Mechanistic Biomarker for Epilepsy.

Tobias Engel.

  Epilepsy, characterized by recurrent spontaneous seizures, is a heterogeneous group of brain diseases affecting over 70 million people worldwide. Major challenges in the management of epilepsy include its diagnosis and treatment. To date, video electroencephalogram (EEG) monitoring is the gold-standard diagnostic method, with no molecular biomarker in routine clinical use. Moreover, treatment based on anti-seizure medications (ASMs) remains ineffective in 30% of patients, and, even if seizure-suppressive, lacks disease-modifying potential. Current epilepsy research is, therefore, mainly focussed on the identification of new drugs with a different mechanism of action effective in patients not responding to current ASMs. The vast heterogeneity of epilepsy syndromes, including differences in underlying pathology, comorbidities and disease progression, represents, however, a particular challenge in drug discovery. Optimal treatment most likely requires the identification of new drug targets combined with diagnostic methods to identify patients in need of a specific treatment. Purinergic signalling via extracellularly released ATP is increasingly recognized to contribute to brain hyperexcitability and, consequently, drugs targeting this signalling system have been proposed as a new therapeutic strategy for epilepsy. Among the purinergic ATP receptors, the P2X7 receptor (P2X7R) has attracted particular attention as a novel target for epilepsy treatment, with P2X7Rs contributing to unresponsiveness to ASMs and drugs targeting the P2X7R modulating acute seizure severity and suppressing seizures during epilepsy. In addition, P2X7R expression has been reported to be altered in the brain and circulation in experimental models of epilepsy and patients, making it both a potential therapeutic and diagnostic target. The present review provides an update on the newest findings regarding P2X7R-based treatments for epilepsy and discusses the potential of P2X7R as a mechanistic biomarker.

Keywords:  P2X7 receptor; diagnosis; epilepsy; purinergic signalling; seizures; treatment

DOI:  https://doi.org/10.3390/ijms24065410
Epilepsy Behav. 2023 Mar 29. pii: S1525-5050(23)00100-2. [Epub ahead of print]142 109181

Treatment of neurometabolic epilepsies: Overview and recent advances.

Itay Tokatly Latzer, Phillip L Pearl.

  The rarity and heterogeneity of neurometabolic diseases make it challenging to reach evidence-based principles for their specific treatments. Indeed, current treatments for many of these diseases remain symptomatic and supportive. However, an ongoing scientific and medical revolution has led to dramatic breakthroughs in molecular sciences and genetics, revealing precise pathophysiologic mechanisms. Accordingly, this has led to significant progress in the development of novel therapeutic approaches aimed at treating epilepsy resulting from these conditions, as well as their other manifestations. We overview recent notable treatment advancements, from vitamins, trace minerals, and diets to unique medications targeting the elemental pathophysiology at a molecular or cellular level, including enzyme replacement therapy, enzyme enhancing therapy, antisense oligonucleotide therapy, stem cell transplantation, and gene therapy.

Keywords:  Inborn errors of metabolism; Metabolic; Progress; Therapy; Update

DOI:  https://doi.org/10.1016/j.yebeh.2023.109181