scholarly journals Advances in mt-tRNA Mutation-Caused Mitochondrial Disease Modeling: Patients’ Brain in a Dish

2021 ◽  
Vol 11 ◽  
Author(s):  
Suleva Povea-Cabello ◽  
Marina Villanueva-Paz ◽  
Juan M. Suárez-Rivero ◽  
Mónica Álvarez-Córdoba ◽  
Irene Villalón-García ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Disease Modeling ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Mitochondrial Diseases ◽  
Pathological Feature ◽  
Mtdna Mutations ◽  
Induced Pluripotent ◽  
Induced Neurons ◽  
Merrf Syndrome

Mitochondrial diseases are a heterogeneous group of rare genetic disorders that can be caused by mutations in nuclear (nDNA) or mitochondrial DNA (mtDNA). Mutations in mtDNA are associated with several maternally inherited genetic diseases, with mitochondrial dysfunction as a main pathological feature. These diseases, although frequently multisystemic, mainly affect organs that require large amounts of energy such as the brain and the skeletal muscle. In contrast to the difficulty of obtaining neuronal and muscle cell models, the development of induced pluripotent stem cells (iPSCs) has shed light on the study of mitochondrial diseases. However, it is still a challenge to obtain an appropriate cellular model in order to find new therapeutic options for people suffering from these diseases. In this review, we deepen the knowledge in the current models for the most studied mt-tRNA mutation-caused mitochondrial diseases, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and MERRF (myoclonic epilepsy with ragged red fibers) syndromes, and their therapeutic management. In particular, we will discuss the development of a novel model for mitochondrial disease research that consists of induced neurons (iNs) generated by direct reprogramming of fibroblasts derived from patients suffering from MERRF syndrome. We hypothesize that iNs will be helpful for mitochondrial disease modeling, since they could mimic patient’s neuron pathophysiology and give us the opportunity to correct the alterations in one of the most affected cellular types in these disorders.

Functional Analysis of PTH1R Variants Found in Primary Failure of Eruption

2020 ◽  
Vol 99 (4) ◽  
pp. 429-436
Author(s):  
E. Izumida ◽  
T. Suzawa ◽  
Y. Miyamoto ◽  
A. Yamada ◽  
M. Otsu ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Disease Modeling ◽  
Lentiviral Vector ◽  
Genetic Disorders ◽  
Induced Pluripotent Stem Cell ◽  
Osteoblastic Differentiation ◽  
Bone Morphogenetic Protein 2 ◽  
Primary Failure Of Eruption ◽  
Key Factor ◽  
Induced Pluripotent

Although many variants of the parathyroid hormone 1 receptor (PTH1R) gene are known to be associated with primary failure of eruption (PFE), the mechanisms underlying the link remains poorly understood. We here performed functional analyses of PTH1R variants reported in PFE patients—namely, 356C>T (P119L), 395C>T (P132L), 439C>T (R147C), and 1148G>A (R383Q)—using HeLa cells with a lentiviral vector-mediated genetic modification. Two particular variants, P119L and P132L, had severe reduction in a level of N-linked glycosylation when compared with wild-type PTH1R, whereas the other 2 showed modest alteration. PTH1R having P119L or P132L showed marked decrease in the affinity to PTH1-34, which likely led to severely impaired cAMP accumulation upon stimulation in cells expressing these mutants, highlighting the importance of these 2 amino acid residues for ligand-mediated proper functioning of PTH1R. To further gain insights into PTH1R functions, we established the induced pluripotent stem cell (iPSC) lines from a patient with PFE and the heterozygous P132L mutation. When differentiated into osteoblastic-lineage cells, PFE-iPSCs showed no abnormality in mineralization. The mRNA expression of RUNX2, SP7, and BGLAP, the osteoblastic differentiation-related genes, and that of PTH1R were augmented in both PFE-iPSC-derived cells and control iPSC-derived cells in the presence of bone morphogenetic protein 2. Also, active vitamin D3 induced the expression of RANKL, a major key factor for osteoclastogenesis, equally in osteoblastic cells derived from control and PFE-iPSCs. In sharp contrast, exposure to PTH1-34 resulted in no induction of RANKL mRNA expression in the cells expressing P132L variant PTH1R, consistent with the idea that a type of heterozygous PTH1R gene mutation would spoil PTH-dependent response in osteoblasts. Collectively, this study demonstrates a link between PFE-associated genetic alteration and causative functional impairment of PTH1R, as well as a utility of iPSC-based disease modeling for future elucidation of pathogenesis in genetic disorders, including PFE.

scholarly journals Reprogramming of EBV-immortalized B-lymphocyte cell lines into induced pluripotent stem cells

Blood ◽  
2011 ◽  
Vol 118 (7) ◽  
pp. 1801-1805 ◽  
Author(s):  
Su Mi Choi ◽  
Hua Liu ◽  
Pooja Chaudhari ◽  
Yonghak Kim ◽  
Linzhao Cheng ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
B Lymphocyte ◽  
Disease Modeling ◽  
Genetic Disorders ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Inherited Disease ◽  
Induced Pluripotent ◽  
Lymphocyte Cell

AbstractEBV-immortalized B lymphocyte cell lines have been widely banked for studying a variety of diseases, including rare genetic disorders. These cell lines represent an important resource for disease modeling with the induced pluripotent stem cell (iPSC) technology. Here we report the generation of iPSCs from EBV-immortalized B-cell lines derived from multiple inherited disease patients via a nonviral method. The reprogramming method for the EBV cell lines involves a distinct protocol compared with that of patient fibroblasts. The B-cell line–derived iPSCs expressed pluripotency markers, retained the inherited mutation and the parental V(D)J rearrangement profile, and differentiated into all 3 germ layer cell types. There was no integration of the reprogramming-related transgenes or the EBV-associated genes in these iPSCs. The ability to reprogram the widely banked patient B-cell lines will offer an unprecedented opportunity to generate human disease models and provide novel drug therapies.

scholarly journals Diagnosis of ‘possible’ mitochondrial disease: an existential crisis

2019 ◽  
Vol 56 (3) ◽  
pp. 123-130 ◽  
Author(s):  
Sumit Parikh ◽  
Amel Karaa ◽  
Amy Goldstein ◽  
Enrico Silvio Bertini ◽  
Patrick F Chinnery ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Clinical Phenotype ◽  
Genetic Disorders ◽  
Genetic Diagnosis ◽  
Mitochondrial Diseases ◽  
Genomic Testing ◽  
Existential Crisis ◽  
Specific Description ◽  
Genetic Abnormalities ◽  
Biochemical Abnormalities

Primary genetic mitochondrial diseases are often difficult to diagnose, and the term ‘possible’ mitochondrial disease is used frequently by clinicians when such a diagnosis is suspected. There are now many known phenocopies of mitochondrial disease. Advances in genomic testing have shown that some patients with a clinical phenotype and biochemical abnormalities suggesting mitochondrial disease may have other genetic disorders. In instances when a genetic diagnosis cannot be confirmed, a diagnosis of ‘possible’ mitochondrial disease may result in harm to patients and their families, creating anxiety, delaying appropriate diagnosis and leading to inappropriate management or care. A categorisation of ‘diagnosis uncertain’, together with a specific description of the metabolic or genetic abnormalities identified, is preferred when a mitochondrial disease cannot be genetically confirmed.

scholarly journals Mitochondrial Dysfunction in Advanced Liver Disease: Emerging Concepts

2021 ◽  
Vol 8 ◽  
Author(s):  
Ingrid W. Zhang ◽  
Cristina López-Vicario ◽  
Marta Duran-Güell ◽  
Joan Clària
Keyword(s):  
Liver Cirrhosis ◽  
Liver Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Mitochondrial Diseases ◽  
Special Focus ◽  
Decompensated Liver Cirrhosis ◽  
Acute Decompensation

Mitochondria are entrusted with the challenging task of providing energy through the generation of ATP, the universal cellular currency, thereby being highly flexible to different acute and chronic nutrient demands of the cell. The fact that mitochondrial diseases (genetic disorders caused by mutations in the nuclear or mitochondrial genome) manifest through a remarkable clinical variation of symptoms in affected individuals underlines the far-reaching implications of mitochondrial dysfunction. The study of mitochondrial function in genetic or non-genetic diseases therefore requires a multi-angled approach. Taking into account that the liver is among the organs richest in mitochondria, it stands to reason that in the process of unravelling the pathogenesis of liver-related diseases, researchers give special focus to characterizing mitochondrial function. However, mitochondrial dysfunction is not a uniformly defined term. It can refer to a decline in energy production, increase in reactive oxygen species and so forth. Therefore, any study on mitochondrial dysfunction first needs to define the dysfunction to be investigated. Here, we review the alterations of mitochondrial function in liver cirrhosis with emphasis on acutely decompensated liver cirrhosis and acute-on-chronic liver failure (ACLF), the latter being a form of acute decompensation characterized by a generalized state of systemic hyperinflammation/immunosuppression and high mortality rate. The studies that we discuss were either carried out in liver tissue itself of these patients, or in circulating leukocytes, whose mitochondrial alterations might reflect tissue and organ mitochondrial dysfunction. In addition, we present different methodological approaches that can be of utility to address the diverse aspects of hepatocyte and leukocyte mitochondrial function in liver disease. They include assays to measure metabolic fluxes using the comparatively novel Biolog’s MitoPlates in a 96-well format as well as assessment of mitochondrial respiration by high-resolution respirometry using Oroboros’ O2k-technology and Agilent Seahorse XF technology.

scholarly journals Mitochondrial Medicine: Genetic Underpinnings and Disease Modeling Using Induced Pluripotent Stem Cell Technology

2021 ◽  
Vol 7 ◽  
Author(s):  
Parisa K. Kargaran ◽  
Diogo Mosqueira ◽  
Tamas Kozicz
Keyword(s):  
Mitochondrial Genome ◽  
Disease Modeling ◽  
Nuclear Genome ◽  
Induced Pluripotent Stem Cell ◽  
Mitochondrial Diseases ◽  
Potential Candidate ◽  
Cellular Models ◽  
Mitochondrial Medicine ◽  
Induced Pluripotent

Mitochondrial medicine is an exciting and rapidly evolving field. While the mitochondrial genome is small and differs from the nuclear genome in that it is circular and free of histones, it has been implicated in neurodegenerative diseases, type 2 diabetes, aging and cardiovascular disorders. Currently, there is a lack of efficient treatments for mitochondrial diseases. This has promoted the need for developing an appropriate platform to investigate and target the mitochondrial genome. However, developing these therapeutics requires a model system that enables rapid and effective studying of potential candidate therapeutics. In the past decade, induced pluripotent stem cells (iPSCs) have become a promising technology for applications in basic science and clinical trials, and have the potential to be transformative for mitochondrial drug development. Engineered iPSC-derived cardiomyocytes (iPSC-CM) offer a unique tool to model mitochondrial disorders. Additionally, these cellular models enable the discovery and testing of novel therapeutics and their impact on pathogenic mtDNA variants and dysfunctional mitochondria. Herein, we review recent advances in iPSC-CM models focused on mitochondrial dysfunction often causing cardiovascular diseases. The importance of mitochondrial disease systems biology coupled with genetically encoded NAD+/NADH sensors is addressed toward developing an in vitro translational approach to establish effective therapies.

scholarly journals Impaired ROS Scavenging System in Human Induced Pluripotent Stem Cells Generated from Patients with MERRF Syndrome

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Shih-Jie Chou ◽  
Wei-Lien Tseng ◽  
Chien-Tsun Chen ◽  
Yu-Fen Lai ◽  
Chian-Shiu Chien ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Ros Scavenging ◽  
Induced Pluripotent ◽  
Merrf Syndrome

scholarly journals Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases

2021 ◽  
Vol 22 (15) ◽  
pp. 8196
Author(s):  
Dorit Trudler ◽  
Swagata Ghatak ◽  
Stuart A. Lipton
Keyword(s):  
Drug Discovery ◽  
Animal Models ◽  
Neurodegenerative Diseases ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Neural Function ◽  
Neural Cells ◽  
Human Samples ◽  
Healthy Donors ◽  
Induced Pluripotent

Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.

scholarly journals Recent Advances in Disease Modeling and Drug Discovery for Diabetes Mellitus Using Induced Pluripotent Stem Cells

2016 ◽  
Vol 17 (2) ◽  
pp. 256 ◽  
Author(s):  
Mohammed Kawser Hossain ◽  
Ahmed Abdal Dayem ◽  
Jihae Han ◽  
Subbroto Kumar Saha ◽  
Gwang-Mo Yang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Stem Cells ◽  
Drug Discovery ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Disease Modeling ◽  
Recent Advances ◽  
Induced Pluripotent
Sign in / Sign up

Export Citation Format

Share Document