bims-curels Biomed News
on Leigh syndrome
Issue of 2023‒09‒24
ten papers selected by
Cure Mito Foundation

  1. J Biomed Sci. 2023 Sep 22. 30(1): 82
      Mitochondria are essential organelles for cellular metabolism and physiology in eukaryotic cells. Human mitochondria have their own genome (mtDNA), which is maternally inherited with 37 genes, encoding 13 polypeptides for oxidative phosphorylation, and 22 tRNAs and 2 rRNAs for translation. mtDNA mutations are associated with a wide spectrum of degenerative and neuromuscular diseases. However, the pathophysiology of mitochondrial diseases, especially for threshold effect and tissue specificity, is not well understood and there is no effective treatment for these disorders. Especially, the lack of appropriate cell and animal disease models has been significant obstacles for deep elucidating the pathophysiology of maternally transmitted diseases and developing the effective therapy approach. The use of human induced pluripotent stem cells (iPSCs) derived from patients to obtain terminally differentiated specific lineages such as inner ear hair cells is a revolutionary approach to deeply understand pathogenic mechanisms and develop the therapeutic interventions of mitochondrial disorders. Here, we review the recent advances in patients-derived iPSCs as ex vivo models for mitochondrial diseases. Those patients-derived iPSCs have been differentiated into specific targeting cells such as retinal ganglion cells and eventually organoid for the disease modeling. These disease models have advanced our understanding of the pathophysiology of maternally inherited diseases and stepped toward therapeutic interventions for these diseases.
    Keywords:  Maternally inherited diseases; Mitochondria; iPSCs; mtDNA mutations
  2. Assist Inferm Ric. 2023 Jul-Sep;42(3):42(3): 152-157
      . Patient and public involvement in research. Patient and public involvement (PPI) entails research being carried out 'with' members of the public, rather than 'to', 'about' or 'for' them. The word public can refer to patients, potential patients, carers and people who use health and social care services, people from organisations that represent people who use services as well as members of the public. People with lived experience of a particular service or health condition may add value to the research and even influence the research question. The involvement may occurr in any stage of the research process, but preferably since the very start, when the study is designed. To obtain a real involvement and participation some practical tips are suggested. In this paper advantages but also difficulties related to PPI are presented, based both on the literature but also from the authors' experience.
  3. CMAJ Open. 2023 Sep-Oct;11(5):11(5): E826-E837
      BACKGROUND: There are few data on patient and public involvement (PPI) in pragmatic trials. We aimed to describe the prevalence and nature of PPI within pragmatic trials, describe variation in prevalence of PPI by trial characteristics and compare prevalence of PPI reported by trial authors to that reported in trial publications.METHODS: We applied a search filter to identify pragmatic trials published from 2014 to 2019 in MEDLINE. We invited the corresponding authors of pragmatic trials to participate in an online survey about their specific trial.
    RESULTS: Of 3163 authors invited, 2585 invitations were delivered, 710 (27.5%) reported on 710 unique trials and completed the survey; 334 (47.0%) conducted PPI. Among those who conducted PPI, for many the aim was to increase the research relevance (86.3%) or quality (76.5%). Most PPI partners were engaged at protocol development stages (79.1%) and contributed to the co-design of interventions (70.9%) or recruitment or retention strategies (60.5%). Patient and public involvement was more common among trials involving children, trials conducted in the United Kingdom, cluster randomized trials, those explicitly labelled as "pragmatic" in the study manuscript, and more recent trials. Less than one-quarter of trials (22.8%) that reported PPI in the survey also reported PPI in the trial manuscript.
    INTERPRETATION: Nearly half of trialists in this survey reported conducting PPI and listed several benefits of doing so, but researchers who did not conduct PPI often cited a lack of requirement for it. Patient and public involvement appears to be significantly underreported in trial publications. Consistent and standardized reporting is needed to promote transparency about PPI methods, outcomes, challenges and benefits.
  4. J Educ Health Promot. 2023 ;12 224
      BACKGROUND: The low prevalence of rare diseases has caused the need for studies in this field to be neglected. Regardless of the prevalence of rare diseases, many people around the world have to live with the medical, psychological, and social consequences of their condition. Individuals with rare diseases may face challenges that are different from those experienced in more common medical conditions. The life experiences of patients with rare diseases have not been sufficiently investigated. The purpose of this study was to discover the meaning of living as a person with a rare disease.MATERIALS AND METHODS: This interpretative phenomenological study was conducted in 2021-2022 on 10 patients with one of the rare diseases (registered in the Atlas of Rare Diseases of Iran). Based on purposeful sampling, people with rare diseases living in Mazandaran, Golestan, and Tehran provinces were invited to participate in the study. Data collection was done using open and semi-structured interviews. The research question was exploring understanding the experience and meaning of life as a person with a rare disease. Van Manen's interpretive phenomenological approach was used to analyze the data, and the criteria of validity, transferability, and verifiability were used to ensure the trustworthiness of the research.
    RESULTS: The five main themes "permanent suffering, such as a bird in a cage, rejection, immersion in the whirlpool of thoughts, losing the feeling of life", and 10 sub-themes "nightmare, giving up, deprivation, limitation, worthlessness, being stigmatized, dark vision, confusion, continuous regret, and inferiority feeling" were extracted.
    CONCLUSION: The results of this study show that the suffering of the disease casts a shadow on all aspects of a patient's life with a rare disease. The effects of illness, disability, limitations, and exclusions had created a human being in a cage, whose right to live like others has been denied.
    Keywords:  Lived experience; phenomenology; qualitative study; rare disease
  5. Ther Innov Regul Sci. 2023 Sep 18.
      BACKGROUND: Conducting of clinical trials for rare diseases faces multiple challenges. Patients' cognition and attitude toward clinical trials are crucial, which may affect their participation and compliance, and affect the schedule of clinical trials eventually.OBJECTIVE AND METHOD: This study aims to explore the knowledge and attitudes of clinical trials of patients with rare diseases or patients' guardians. An anonymous cross-sectional survey was conducted from November 1, 2021, to November 30, 2021. A total of 1131 valid questionnaires were included. Among them, 417 were filled in by the patients themselves, and 714 were answered by the patients' guardians.
    RESULTS: The average score of clinical trial knowledge of the patients (8.25) was lower than that of the guardians (8.85). The willingness of the patients to participate in clinical trials was high (4.28), and the willingness of the patients' guardians was also high for patients to participate in clinical trials (4.35). The main promoting factors of clinical trial participation were the possibility of curing the disease. The main hindering factors of participation in clinical trials were lack of access to clinical trial information and concern about the safety and effectiveness of the trial drug.
    CONCLUSIONS: In conclusion, most respondents had some basic knowledge of clinical trials and high willingness to participate in clinical trials. But there were some cognitive deficiencies about clinical trials and many hindering factors to participate in clinical trials. Clinical trials of rare diseases should be patient-centered and truly meet the unmet clinical, psychological, and social needs of patients with rare diseases.
    Keywords:  Attitude; Clinical trial; Knowledge; Rare disease
  6. Intern Med J. 2023 Sep 21.
      BACKGROUND: The complexities of mitochondrial disease make epidemiological studies challenging, yet this information is important in understanding the healthcare burden and addressing service and educational needs. Existing studies are limited to quaternary centres or focus on a single genotype or phenotype and estimate disease prevalence at 12.5 per 100 000. New Zealand's (NZ) size and partially integrated national healthcare system make it amenable to a nationwide prevalence study.AIM: To estimate the prevalence of molecularly confirmed and suspected mitochondrial disease on 31 December 2015 in NZ.
    METHODS: Cases were identified from subspecialists and laboratory databases and through interrogation of the Ministry of Health National Minimum Dataset with a focus on presentations between 2000 and 2015. Patient records were reviewed, and those with a diagnosis of 'mitochondrial disease' who were alive and residing in NZ on the prevalence date were included. These were divided into molecularly confirmed and clinically suspected cases. Official NZ estimated resident population data were used to calculate prevalence.
    RESULTS: Seven hundred twenty-three unique national health index numbers were identified. Five hundred five were excluded. The minimum combined prevalence for mitochondrial disease was 4.7 per 100 000 (95% confidence interval (CI): 4.1-5.4). The minimum prevalence for molecularly confirmed and suspected disease was 2.9 (95% CI 2.4-3.4) and 1.8 (95% CI 1.4-2.2) cases per 100 000 respectively.
    CONCLUSIONS: Within the limitations of this study, comparison to similar prevalence studies performed by specialist referral centres suggests mitochondrial disease is underdiagnosed in NZ. This highlights a need for improved education and referral pathways for mitochondrial disease in NZ.
    Keywords:  New Zealand/epidemiology*; mitochondrial diseases/diagnosis*; mitochondrial diseases/epidemiology*; mutation/genetics*; prevalence
  7. Front Cell Dev Biol. 2023 ;11 1257651
      The mitochondrion is a major hub of cellular metabolism and involved directly or indirectly in almost all biological processes of the cell. In mitochondrial diseases, compromised respiratory electron transfer and oxidative phosphorylation (OXPHOS) lead to compensatory rewiring of metabolism with resemblance to the Warburg-like metabolic state of cancer cells. The transcription factor MYC (or c-MYC) is a major regulator of metabolic rewiring in cancer, stimulating glycolysis, nucleotide biosynthesis, and glutamine utilization, which are known or predicted to be affected also in mitochondrial diseases. Albeit not widely acknowledged thus far, several cell and mouse models of mitochondrial disease show upregulation of MYC and/or its typical transcriptional signatures. Moreover, gene expression and metabolite-level changes associated with mitochondrial integrated stress response (mt-ISR) show remarkable overlap with those of MYC overexpression. In addition to being a metabolic regulator, MYC promotes cellular proliferation and modifies the cell cycle kinetics and, especially at high expression levels, promotes replication stress and genomic instability, and sensitizes cells to apoptosis. Because cell proliferation requires energy and doubling of the cellular biomass, replicating cells should be particularly sensitive to defective OXPHOS. On the other hand, OXPHOS-defective replicating cells are predicted to be especially vulnerable to high levels of MYC as it facilitates evasion of metabolic checkpoints and accelerates cell cycle progression. Indeed, a few recent studies demonstrate cell cycle defects and nuclear DNA damage in OXPHOS deficiency. Here, we give an overview of key mitochondria-dependent metabolic pathways known to be regulated by MYC, review the current literature on MYC expression in mitochondrial diseases, and speculate how its upregulation may be triggered by OXPHOS deficiency and what implications this has for the pathogenesis of these diseases.
    Keywords:  Warburg effect; cellular senescence; electron transport chain; mitochondrial integrated stress response; oxidative phosphorylation; respiratory complex III
  8. Am J Manag Care. 2023 Sep;29(9): 437-438
      This commentary explores what matters to patients and their experience through an equity lens, with action points and recommendations given the current health care environment.
  9. bioRxiv. 2023 Sep 05. pii: 2023.09.01.555986. [Epub ahead of print]
      Mitochondrial DNA (mtDNA) mutations are frequently observed in cancer, but their contribution to tumor progression is controversial. To evaluate the impact of mtDNA variants on tumor growth and metastasis, we created human melanoma cytoplasmic hybrid (cybrid) cell lines transplanted with wildtype mtDNA or pathogenic mtDNA encoding variants that partially or completely inhibit oxidative phosphorylation. Homoplasmic pathogenic mtDNA cybrids reliably established tumors despite dysfunctional oxidative phosphorylation. However, pathogenic mtDNA variants disrupted spontaneous metastasis of subcutaneous tumors and decreased the abundance of circulating melanoma cells in the blood. Pathogenic mtDNA did not induce anoikis or inhibit organ colonization of melanoma cells following intravenous injections. Instead, migration and invasion were reduced, indicating that limited circulation entry functions as a metastatic bottleneck amidst mtDNA dysfunction. Furthermore, analysis of selective pressure exerted on the mitochondrial genomes of heteroplasmic cybrid lines revealed a suppression of pathogenic mtDNA allelic frequency during melanoma growth. Collectively, these findings demonstrate that functional mtDNA is favored during melanoma growth and enables metastatic entry into the blood.