bims-curels Biomed News
on Leigh syndrome
Issue of 2024‒10‒13
eight papers selected by
Cure Mito Foundation
  1. Disease models of Leigh syndrome: From yeast to organoids.
  2. [Taurine for Mitochondrial Diseases].
  3. Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition.
  4. Nuclear compensatory evolution driven by mito-nuclear incompatibilities.
  5. A platform to map the mind-mitochondria connection and the hallmarks of psychobiology: the MiSBIE study.
  6. What's it like to be a patient as a doctor?
  7. SLC6A1 patient & organization perspective: founding of SLC6A1 connect, research, and ongoing efforts.
  8. A roadmap to cure CHD2-related disorders.
  1. J Inherit Metab Dis. 2024 Oct 09.
    Disease models of Leigh syndrome: From yeast to organoids.
    Marie-Thérèse Henke, Alessandro Prigione, Markus Schuelke.
      Leigh syndrome (LS) is a severe mitochondrial disease that results from mutations in the nuclear or mitochondrial DNA that impairs cellular respiration and ATP production. Mutations in more than 100 genes have been demonstrated to cause LS. The disease most commonly affects brain development and function, resulting in cognitive and motor impairment. The underlying pathogenesis is challenging to ascertain due to the diverse range of symptoms exhibited by affected individuals and the variability in prognosis. To understand the disease mechanisms of different LS-causing mutations and to find a suitable treatment, several different model systems have been developed over the last 30 years. This review summarizes the established disease models of LS and their key findings. Smaller organisms such as yeast have been used to study the biochemical properties of causative mutations. Drosophila melanogaster, Danio rerio, and Caenorhabditis elegans have been used to dissect the pathophysiology of the neurological and motor symptoms of LS. Mammalian models, including the widely used Ndufs4 knockout mouse model of complex I deficiency, have been used to study the developmental, cognitive, and motor functions associated with the disease. Finally, cellular models of LS range from immortalized cell lines and trans-mitochondrial cybrids to more recent model systems such as patient-derived induced pluripotent stem cells (iPSCs). In particular, iPSCs now allow studying the effects of LS mutations in specialized human cells, including neurons, cardiomyocytes, and even three-dimensional organoids. These latter models open the possibility of developing high-throughput drug screens and personalized treatments based on defined disease characteristics captured in the context of a defined cell type. By analyzing all these different model systems, this review aims to provide an overview of past and present means to elucidate the complex pathology of LS. We conclude that each approach is valid for answering specific research questions regarding LS, and that their complementary use could be instrumental in finding treatment solutions for this severe and currently untreatable disease.
    Keywords:  Leigh syndrome; animal models; disease modeling; mitochondrial diseases; organoids; phenotyping; pluripotent stem cells
    DOI:  https://doi.org/10.1002/jimd.12804
  2. Brain Nerve. 2024 Oct;76(10): 1127-1135
    [Taurine for Mitochondrial Diseases].
    Yoshihide Sunada.
      Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is characterized by a mitochondrial DNA mutation that leads to defective taurine modification of the leucine tRNA anticodon, with consequent impaired translation of the UUG codon. This defect reduces synthesis of respiratory chain complexes, which causes energy failure. Taurine supplementation improved mitochondrial function in MELAS model cells. A physician-initiated clinical trial reported that high-dose taurine supplementation therapy suppressed stroke-like episodes and improved taurine modification rates in leukocytes.
    DOI:  https://doi.org/10.11477/mf.1416202748
  3. Nat Commun. 2024 Oct 07. 15(1): 8682
    Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition.
    Lucia Del Prado, Myriam Jaraíz-Rodríguez, Mauro Agro, Marcos Zamora-Dorta, Natalia Azpiazu, Manuel Calleja, Mario Lopez-Manzaneda, Jaime de Juan-Sanz, Alba Fernández-Rodrigo, José A Esteban, Mònica Girona, Albert Quintana, Eduardo Balsa.
      Deficiencies in the electron transport chain (ETC) lead to mitochondrial diseases. While mutations are distributed across the organism, cell and tissue sensitivity to ETC disruption varies, and the molecular mechanisms underlying this variability remain poorly understood. Here we show that, upon ETC inhibition, a non-canonical tricarboxylic acid (TCA) cycle upregulates to maintain malate levels and concomitant production of NADPH. Our findings indicate that the adverse effects observed upon CI inhibition primarily stem from reduced NADPH levels, rather than ATP depletion. Furthermore, we find that Pyruvate carboxylase (PC) and ME1, the key mediators orchestrating this metabolic reprogramming, are selectively expressed in astrocytes compared to neurons and underlie their differential sensitivity to ETC inhibition. Augmenting ME1 levels in the brain alleviates neuroinflammation and corrects motor function and coordination in a preclinical mouse model of CI deficiency. These studies may explain why different brain cells vary in their sensitivity to ETC inhibition, which could impact mitochondrial disease management.
    DOI:  https://doi.org/10.1038/s41467-024-52968-1
  4. Proc Natl Acad Sci U S A. 2024 Oct 15. 121(42): e2411672121
    Nuclear compensatory evolution driven by mito-nuclear incompatibilities.
    Debora Princepe, Marcus A M de Aguiar.
      Mitochondrial function relies on the coordinated expression of mitochondrial and nuclear genes, exhibiting remarkable resilience despite high mitochondrial mutation rates. The nuclear compensation mechanism suggests deleterious mitochondrial alleles drive compensatory nuclear mutations to preserve mito-nuclear compatibility. However, prevalence and factors conditioning this phenomenon remain debated due to its conflicting evidence. Here, we investigate how mito-nuclear incompatibilities impact substitutions in a model for species radiation. Mating success depends on genetic compatibility (nuclear DNA) and spatial proximity. Populations evolve from partially compatible mito-nuclear states, simulating mitochondrial DNA (mtDNA) introgression. Mutations do not confer advantages nor disadvantages, but individual fecundity declines with increasing incompatibilities, selecting for mito-nuclear coordination. We find that selection for mito-nuclear compatibility affects each genome differently based on their initial state. In compatible gene pairs, selection reduces substitutions in both genomes, while in incompatible nuclear genes, it consistently promotes compensation, facilitated by more mismatches. Interestingly, high mitochondrial mutation rates can reduce nuclear compensation by increasing mtDNA rectification, while substitutions in initially compatible nuclear gene are boosted. Finally, the presence of incompatibilities accelerates species radiation, but equilibrium richness is not directly correlated to substitution rates, revealing the complex dynamics triggered by mitochondrial introgression and mito-nuclear coevolution. Our study provides a perspective on nuclear compensation and the role of mito-nuclear incompatibilities in speciation by exploring extreme scenarios and identifying trends that empirical data alone cannot reveal. We emphasize the challenges in detecting these dynamics and propose analyzing specific genomic signatures could shed light on this evolutionary process.
    Keywords:  mito-nuclear coevolution; mitochondrial mutation rate; mtDNA introgression; nuclear compensation
    DOI:  https://doi.org/10.1073/pnas.2411672121
  5. Trends Endocrinol Metab. 2024 Oct 09. pii: S1043-2760(24)00225-X. [Epub ahead of print]
    A platform to map the mind-mitochondria connection and the hallmarks of psychobiology: the MiSBIE study.
    MiSBIE Study Group
      Health emerges from coordinated psychobiological processes powered by mitochondrial energy transformation. But how do mitochondria regulate the multisystem responses that shape resilience and disease risk across the lifespan? The Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE) study was established to address this question and determine how mitochondria influence the interconnected neuroendocrine, immune, metabolic, cardiovascular, cognitive, and emotional systems among individuals spanning the spectrum of mitochondrial energy transformation capacity, including participants with rare mitochondrial DNA (mtDNA) lesions causing mitochondrial diseases (MitoDs). This interdisciplinary effort is expected to generate new insights into the pathophysiology of MitoDs, provide a foundation to develop novel biomarkers of human health, and integrate our fragmented knowledge of bioenergetic, brain-body, and mind-mitochondria processes relevant to medicine and public health.
    Keywords:  allostasis; metabolism; mitochondrial disorders; mtDNA; psychobiology; stress
    DOI:  https://doi.org/10.1016/j.tem.2024.08.006
  6. BMJ. 2024 Oct 11. 387 q1486
    What's it like to be a patient as a doctor?
    Jo Best.
      
    DOI:  https://doi.org/10.1136/bmj.q1486
  7. Ther Adv Rare Dis. 2024 Jan-Dec;5:5 26330040241283734
    SLC6A1 patient & organization perspective: founding of SLC6A1 connect, research, and ongoing efforts.
    Jacob Tiller, Melissa B DeLeeuw, Jing-Qiong Kang, Amber Freed.
      This paper describes the founding of the SLC6A1 Connect organization, which offers resources to patients and families with SLC6A1 diagnoses while keeping current with a scientific overview of the disorder. Following the birth of her two lovely twins, Amber Freed noticed how her son, Maxwell, missed motor development milestones and would often stare. Eventually, these signs led to a diagnosis of an SLC6A1 variant. The SLC6A1 gene is located on the short arm of chromosome 3 and the gene encodes for the gamma-aminobutyric acid (GABA) transporter 1 (GAT-1) protein. This transporter is responsible for the reuptake of the inhibitory neurotransmitter, GABA. The transporter usually removes GABA from the synapse space between two neurons, limiting over-excitability in the brain, which can lead to seizures and motor deficits as Amber noticed in her son, Maxwell. Amber realized that there were nearly no treatment options for her son's condition so she began forming connections with scientists and doctors. Initially, she flew to see Dr. Steven Gray, with whom she developed a research plan for a gene replacement therapy to treat the variant along with a design for a clinical trial. Not only this but they needed to raise four million dollars to fund these endeavors. Freed founded the SLC6A1 Connect organization to raise money and awareness and put together a network of dedicated researchers and families. Since then, the organization has raised over two million dollars and grown to offer families a base of support. The organization even hosts a yearly symposium with families, scientists, and biotech or pharmaceutical companies worldwide. In addition, we detail how the organization now offers informational resources to families to help them understand the science behind the variant and ways to help their children such as registry links and genetic testing options. These endeavors have led the organization to collaborate with scientists based on institutions such as Vanderbilt University Medical Center, UT Southwestern Medical Center, the Cleveland Clinic, and many industrial pharmaceutical partners.
    Keywords:  (γ-aminobutyric acid) GABA; GABA Transporter 1 (GAT-1); SLC6A1; motor deficits; neurodevelopmental disorders; rare disease community; seizures
    DOI:  https://doi.org/10.1177/26330040241283734
  8. Ther Adv Rare Dis. 2024 Jan-Dec;5:5 26330040241283749
    A roadmap to cure CHD2-related disorders.
    Stephanie Prince, Emily Bonkowski, Christopher McGraw, Christina SanInocencio, Heather C Mefford, Gemma Carvill, Brian Broadbent.
      Coalition to Cure CHD2 (CCC) is a patient advocacy group dedicated to improving the lives of those affected by CHD2-related disorders (CHD2-RD) by increasing education, building community, and accelerating research to uncover a cure. CHD2 is a chromatin remodeler that was identified in 2013 as being a genetic cause for developmental and epileptic encephalopathies. Pathogenic changes in CHD2 can cause treatment-resistant epilepsy, intellectual and developmental delays, and autism, and some individuals experience neurodevelopmental regression. There are currently no targeted therapies available for CHD2-related disorders. Haploinsufficiency of CHD2 is a causative mechanism of disease for individuals with pathogenic variants (primarily truncating) in CHD2. Recently, identification of individuals with deletion of nearby gene CHASERR, a regulator of CHD2 gene expression, has established dosage sensitivity in CHD2 and solidified the CHASERR gene as a potential therapeutic target for CHD2 levels. Through collaboration with our community and our scientific advisory board, CCC has created a Roadmap to Cure CHD2 as our guide toward a targeted cure that can benefit our community, with steps including (1) identifying and defining patients, (2) developing models of CHD2, (3) studying models of CHD2, (4) testing therapies, (5) involving patients, and (6) reaching a cure. Despite some of the challenges inherent in CHD2 research including establishing animal and cellular models that recapitulate the CHD2 clinical phenotype, identifying measurable outcomes and reliable biomarkers, or testing emerging therapeutic approaches, CCC continues to engage with our community to support ongoing research that aligns with our priorities. CCC sees new and exciting opportunities for additional research that can move our community toward our common goal of a cure that will improve the lives of individuals and their families now and in the future.
    Keywords:  CHASERR; CHD2; DNA Methylation; Developmental and Epileptic Encephalopathy (DEE); epilepsy; long noncoding RNAs; rare disease
    DOI:  https://doi.org/10.1177/26330040241283749
This page is being maintained by Thomas Krichel. It was last updated on 2024‒10‒13 at 17:14.