bims-curels Biomed News
on Leigh syndrome
Issue of 2024–11–03
seven papers selected by
Cure Mito Foundation
  1. A novel m.5906G > a variant in MT-CO1 causes MELAS/Leigh overlap syndrome.
  2. Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.
  3. Comprehensive phenotypic assessment of nonsense mutations in mitochondrial ND5 in mice.
  4. Data professionals' attitudes on data privacy, sharing, and consent in healthcare and research.
  5. Mitochondrial DNA Alterations in Glioblastoma and Current Therapeutic Targets.
  6. In organello silencing of mitochondrial gene expression.
  7. The role of mitochondrial DNA copy number in autoimmune disease: a bidirectional two sample mendelian randomization study.
  1. Mol Genet Genomics. 2024 Oct 26. 299(1): 102
    A novel m.5906G > a variant in MT-CO1 causes MELAS/Leigh overlap syndrome.
    Zhimei Liu, Yaojun Xie, Xiaoting Lou, Xiaofei Zeng, Luyi Zhang, Meng Yu, Junling Wang, Jiuwei Li, Danmin Shen, Hua Li, Suzhou Zhao, Yuwei Zhou, Hezhi Fang, Jianxin Lyu, Yun Yuan, Zhaoxia Wang, Liqin Jin, Fang Fang.
      The MELAS/Leigh overlap syndrome manifests with a blend of clinical and radiographic traits from both MELAS and LS. However, the association of MELAS/Leigh overlap syndrome with MT-CO1 gene variants has not been previously reported. In this study, we report a patient diagnosed with MELAS/Leigh overlap syndrome harboring the m.5906G > A variant in MT-CO1, with biochemical evidence supporting the pathogenicity of the variant. The variant m.5906G > A that led to a synonymous variant in the start codon of MT-CO1 was filtered as the candidate disease-causing variant of the patient. Patient-derived fibroblasts were used to generate a series of monoclonal cells carrying different m.5906G > A variant loads for further functional assays. The oxygen consumption rate, ATP production, mitochondrial membrane potential and lactate assay indicated an impairment of cellular bioenergetics due to the m.5906G > A variant. Blue native PAGE analysis revealed that the m.5906G > A variant caused a deficiency in the content of mitochondrial oxidative phosphorylation complexes. Furthermore, molecular biology assays performed for the pathogenesis, mtDNA copy number, mtDNA-encoded subunits, and recovery capacity of mtDNA were all deficient due to the m.5906G > A variant, which might be caused by mtDNA replication deficiency. Overall, our findings demonstrated the pathogenicity of m.5906G > A variant and proposed a potential pathogenic mechanism, thereby expanding the genetic spectrum of MELAS/Leigh overlap syndrome.
    Keywords:  M.5906G > A; MT-CO1 ; MELAS/Leigh overlap syndrome; MtDNA replication
    DOI:  https://doi.org/10.1007/s00438-024-02181-y
  2. Sci Adv. 2024 Nov;10(44): eadk8801
    Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.
    Spencer D Shelton, Sara House, Luiza Martins Nascentes Melo, Vijayashree Ramesh, Zhenkang Chen, Tao Wei, Xun Wang, Claire B Llamas, Siva Sai Krishna Venigalla, Cameron J Menezes, Gabriele Allies, Jonathan Krystkiewicz, Jonas Rösler, Sven W Meckelmann, Peihua Zhao, Florian Rambow, Dirk Schadendorf, Zhiyu Zhao, Jennifer G Gill, Ralph J DeBerardinis, Sean J Morrison, Alpaslan Tasdogan, Prashant Mishra.
      Mitochondrial DNA (mtDNA) mutations are frequent in cancer, yet their precise role in cancer progression remains debated. To functionally evaluate the impact of mtDNA variants on tumor growth and metastasis, we developed an enhanced cytoplasmic hybrid (cybrid) generation protocol and established isogenic human melanoma cybrid lines with wild-type mtDNA or pathogenic mtDNA mutations with partial or complete loss of mitochondrial oxidative function. Cybrids with homoplasmic levels of pathogenic mtDNA reliably established tumors despite dysfunctional oxidative phosphorylation. However, these mtDNA variants disrupted spontaneous metastasis from primary tumors and reduced the abundance of circulating tumor cells. Migration and invasion of tumor cells were reduced, indicating that entry into circulation is a bottleneck for metastasis amid mtDNA dysfunction. Pathogenic mtDNA did not inhibit organ colonization following intravenous injection. In heteroplasmic cybrid tumors, single-cell analyses revealed selection against pathogenic mtDNA during melanoma growth. Collectively, these findings experimentally demonstrate that functional mtDNA is favored during melanoma growth and supports metastatic entry into the blood.
    DOI:  https://doi.org/10.1126/sciadv.adk8801
  3. Exp Mol Med. 2024 Nov 01.
    Comprehensive phenotypic assessment of nonsense mutations in mitochondrial ND5 in mice.
    Sanghun Kim, Seul Gi Park, Jieun Kim, Seongho Hong, Sang-Mi Cho, Soo-Yeon Lim, Eun-Kyoung Kim, Sungjin Ju, Su Bin Lee, Sol Pin Kim, Tae Young Jeong, Yeji Oh, Seunghun Han, Hae-Rim Kim, Taek Chang Lee, Hyoung-Chin Kim, Won Kee Yoon, Tae Hyeon An, Kyoung-Jin Oh, Ki-Hoan Nam, Seonghyun Lee, Kyoungmi Kim, Je Kyung Seong, Hyunji Lee.
      Mitochondrial dysfunction induced by mitochondrial DNA (mtDNA) mutations has been implicated in various human diseases. A comprehensive analysis of mitochondrial genetic disorders requires suitable animal models for human disease studies. While gene knockout via premature stop codons is a powerful method for investigating the unique functions of target genes, achieving knockout of mtDNA has been rare. Here, we report the genotypes and phenotypes of heteroplasmic MT-ND5 gene-knockout mice. These mutant mice presented damaged mitochondrial cristae in the cerebral cortex, hippocampal atrophy, and asymmetry, leading to learning and memory abnormalities. Moreover, mutant mice are susceptible to obesity and thermogenetic disorders. We propose that these mtDNA gene-knockdown mice could serve as valuable animal models for studying the MT-ND5 gene and developing therapies for human mitochondrial disorders in the future.
    DOI:  https://doi.org/10.1038/s12276-024-01333-9
  4. Digit Health. 2024 Jan-Dec;10:10 20552076241290964
    Data professionals' attitudes on data privacy, sharing, and consent in healthcare and research.
    Katya Kaplow, Max Downey, Darren Stewart, Allan B Massie, Jennifer D Motter, Lauren Taylor, John Massarelli, Taylor Matalon, Carolyn Sidoti, Macey L Levan, Brendan Parent.
       Objective: Individuals who work on health data systems and services are uniquely positioned to understand the risks of health data collection and use. We designed and conducted a survey assessing the perceptions of those who work with health data around health data consent, sharing, and privacy practices in healthcare and clinical research.
    Methods: A 43-item online survey was distributed via a market research firm to individuals (18+) who work with health data in the United States from March to April 2023. Descriptive statistics were calculated for all variables. Associations with demographic variables were assessed using Pearson's X 2 tests and ordinal logistic regression.
    Results: Most of our respondents (61.7%) reported that they would trust people to use their health data across various sectors, but more respondents trusted those working in academic medical research (86.5%) and healthcare offices (89.9%) compared to those working in industry (68.2%). Despite this reported trust, a strong majority believed that individuals should have complete control over their health data (97.3%), specific consent should be obtained for each use of their health data (92.0%), and that there should be higher standards of consent and privacy for health records data than other types of data (93.7%).
    Conclusions: Based on our findings, we might infer that people who work with health data generally trust institutions across sectors to protect their health data. However, many would prefer to have complete control over who has access to their health data and how it is used. These insights should be explored further through qualitative studies.
    Keywords:  Informed consent; bioethics; data sharing; health research; patient data privacy
    DOI:  https://doi.org/10.1177/20552076241290964
  5. Front Biosci (Landmark Ed). 2024 Oct 23. 29(10): 367
    Mitochondrial DNA Alterations in Glioblastoma and Current Therapeutic Targets.
    Maher Kurdi, Ahmed Bamaga, Alaa Alkhotani, Thamer Alsharif, Ghada A Abdel-Hamid, Mohamed E Selim, Taghreed Alsinani, Ahmed Albeshri, Adnan Badahdah, Mazen Basheikh, Saleh Baeesa.
      Metabolic reprogramming within tumor cells involves a shift towards either glycolysis or mitochondrial respiration, depending on the stage of tumor progression. Consequently, irreversible dysfunction of the mitochondria is considered a crucial mechanism driving the progression mechanism. While numerous mutations in mitochondrial DNA (mtDNA) have been identified across various tumor types, including glioblastoma, many studies have been limited in the scope, focusing on small segments of mtDNA or utilizing sequencing methods with restricted sensitivity. As a result, several potentially significant mtDNA mutations may have been underestimated, along with their heteroplasmic states, which play a crucial role in determining the phenotypic impact of mtDNA mutation. Although both somatic and germline mtDNA mutations have been observed in different tumor types, research on the mtDNA mutations linked to glioblastoma remains scarce. The mitochondrial genome encodes thirteen protein-coding genes that are essential for the proper functioning of respiratory complex chains. Alterations in mitochondrial function manifest at various levels, including structural and functional changes, impacting mitogenic, hemodynamic, bioenergetic, and apoptotic signaling pathways. These alterations often signify a reduced efficiency of the oxidative phosphorylation system and energy production in tumor cells. As the crucial role of mitochondrial dysfunction in glioma development grows, mitochondria have emerged as promising targets for therapy aimed at overcoming chemoresistance and eliminating cancer cells. This brief review outlines the association between mtDNA alteration and glioblastoma, as well as the current advancements in therapeutic strategies targeting mtDNA alterations.
    Keywords:  mitochondrial DNA mutation; oxidative phosphorylation glioblastoma; treatment
    DOI:  https://doi.org/10.31083/j.fbl2910367
  6. Methods Enzymol. 2024 ;pii: S0076-6879(24)00371-9. [Epub ahead of print]706 501-518
    In organello silencing of mitochondrial gene expression.
    Mats Koschel, Luis Daniel Cruz-Zaragoza.
      Mitochondria contain proteins from two genetic origins. Most mitochondrial proteins are encoded in the nuclear genome, translated in the cytosol, and subsequently imported into the different mitochondrial sub-compartments. A small number is encoded in the mitochondrial DNA (mtDNA). The manipulation of the mtDNA gene expression represents a challenge. Here, we present an in vitro approach using morpholinos chemically linked to a precursor protein to silence gene expression in purified human mitochondria. The protocol is demonstrated with a Jac1-morpholino chimera specifically targeting COX1 mRNA. The chimera import and mitochondrial translation requirements are described in a step-by-step procedure, where the dose-dependent effect of reducing COX1 translation is observed. The affinity and specificity of chimera-mRNA binding also show great applicability to purify transcript-associated proteins by using the imported chimera construct as bait for immunoprecipitation. This new strategy opens up the possibility to address mechanistic questions about gene expression and physiology in mitochondria.
    Keywords:  Gene expression; In vitro; Mitochondria; Morpholino; Silencing
    DOI:  https://doi.org/10.1016/bs.mie.2024.07.035
  7. Front Immunol. 2024 ;15 1409969
    The role of mitochondrial DNA copy number in autoimmune disease: a bidirectional two sample mendelian randomization study.
    Zhekang Liu, Qingan Fu, Yijia Shao, Xinwang Duan.
       Background: Mitochondrial DNA (mtDNA) plays an important role in autoimmune diseases (AD), yet the relationship between mitochondria and autoimmune disease is controversial. This study employed bidirectional Mendelian randomization (MR) to explore the causal relationship between mtDNA copy number and 13 ADs (including ankylosing spondylitis [AS], Crohn's disease [CD], juvenile rheumatoid arthritis [JRA], polymyalgia rheumatica [PMR], psoriasis [PSO], rheumatoid arthritis [RA], Sjogren's syndrome [SS], systemic lupus erythematosus [SLE], thyrotoxicosis, type 1 diabetes mellitus [T1DM], ulcerative colitis [UC], and vitiligo).
    Methods: A two-sample MR analysis was performed to assess the causal relationship between mtDNA copy number and AD. Genome-wide association study (GWAS) for mtDNA copy number were obtained from the UK Biobank (UKBB), while those associated with AD were sourced from the FinnGen Biobank. Inverse variance weighting (IVW) was the primary analysis method, complemented by three sensitivity analyses (MR-Egger, weighted median, weighted mode) to validate the results.
    Results: IVW MR analysis identified significant associations between mtDNA copy number and CD (OR=2.51, 95% CI 1.56-4.22, P<0.001), JRA (OR=1.87, 95% CI 1.17-7.65, P=0.022), RA (OR=1.71, 95%CI 1.18-2.47, P=0.004), thyrotoxicosis (OR=0.51, 95% CI0.27-0.96, P=0.038), and T1DM (OR=0.51, 95% CI 0.27-0.96, P=0.038). Sensitivity analyses indicated no horizontal pleiotropy.
    Conclusions: Our study revealed a potential causal relationship between mtDNA copy number and ADs, indicating that these markers may be relevant in exploring new therapeutic approaches.
    Keywords:  GWAS; Mendelian randomization; autoimmune disease; causal association; mitochondrial DNA copy number
    DOI:  https://doi.org/10.3389/fimmu.2024.1409969
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