Cardiac Mitochondrial Dysfunction in Leigh Syndrome

1996 ◽  
Vol 17 (6) ◽  
pp. 387-389 ◽  
Author(s):  
J. Marin-Garcia ◽  
R. Ananthakrishnan ◽  
M. Korson ◽  
M.J. Goldenthal ◽  
A. Perez-Atayde
Keyword(s):  
Mitochondrial Dysfunction ◽  
Leigh Syndrome

Modulation of mitochondrial dysfunction-related oxidative stress in fibroblasts of patients with Leigh syndrome by inhibition of prooxidative p66Shc pathway

Mitochondrion ◽  
2017 ◽  
Vol 37 ◽  
pp. 62-79 ◽  
Author(s):  
Aleksandra Wojtala ◽  
Agnieszka Karkucinska-Wieckowska ◽  
Vilma A. Sardao ◽  
Joanna Szczepanowska ◽  
Pawel Kowalski ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Leigh Syndrome

scholarly journals IS AGING AN ACQUIRED MITOCHONDRIAL DISEASE?

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S394-S395
Author(s):  
Alessandro Bitto
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Disease ◽  
Leigh Syndrome ◽  
Childhood Disorders ◽  
Normative Aging ◽  
Similarities And Differences

Abstract Mitochondrial dysfunction is a hallmark of aging, but severe mitochondrial dysfunction leads to rare childhood disorders such as Leigh Syndrome. This session explores the similarities and differences between normative aging and mitochondrial disease and the potential for interventions to positively impact both conditions.

scholarly journals AGING AND MITOCHONDRIAL DISEASE: SHARED MECHANISMS AND THERAPIES?

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S395-S395
Author(s):  
Alessandro Bitto ◽  
Herman Tung ◽  
Kejun Ying ◽  
Daniel L Smith ◽  
Ernst-Bernhard Kayser ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Disease ◽  
Leigh Syndrome ◽  
Disease Suppression ◽  
Nutrient Metabolism ◽  
Disease Symptoms ◽  
Multiple Organs ◽  
Age Related ◽  
Nadh Ubiquinone Oxidoreductase ◽  
Transport Chain

Abstract Mitochondrial disease describes multiple pathologies characterized by a wide array of disease symptoms and severity, caused by mitochondrial dysfunction in one or multiple organs. Aging organisms display a similar variety of disease phenotypes, which are often characterized by mitochondrial impairment. Despite the heterogeneity of aging phenotypes, several interventions have been identified which can increase lifespan and delay the onset of age-related diseases in multiple organisms. Two age-delaying interventions, rapamycin and acarbose, dramatically suppress pathology in a mouse model of mitochondrial disease caused by depletion of the NADH-Ubiquinone Oxidoreductase Complex (Ndufs4-/-). This model recapitulates human Leigh syndrome, a childhood mitochondrial disease. Upon treatment with either drug, disease suppression is accompanied by a remodeling of nutrient metabolism and restoration of the NAD+/NADH ratio in the brain without affecting the electron transport chain. Thus, we propose that metabolic derangements induced by mitochondrial dysfunction may be a shared mechanism of aging and mitochondrial disease.

scholarly journals Mitochondrial retrograde signaling regulates neuronal function

2015 ◽  
Vol 112 (44) ◽  
pp. E6000-E6009 ◽  
Author(s):  
Umut Cagin ◽  
Olivia F. Duncan ◽  
Ariana P. Gatt ◽  
Marc S. Dionne ◽  
Sean T. Sweeney ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Hypoxia Inducible Factor ◽  
Leigh Syndrome ◽  
Retrograde Signaling ◽  
Neuronal Function ◽  
Mitochondrial Retrograde Signaling ◽  
Factor Alpha ◽  
Familial Parkinson’S Disease ◽  
Mitochondrial Defect

Mitochondria are key regulators of cellular homeostasis, and mitochondrial dysfunction is strongly linked to neurodegenerative diseases, including Alzheimer’s and Parkinson’s. Mitochondria communicate their bioenergetic status to the cell via mitochondrial retrograde signaling. To investigate the role of mitochondrial retrograde signaling in neurons, we induced mitochondrial dysfunction in the Drosophila nervous system. Neuronal mitochondrial dysfunction causes reduced viability, defects in neuronal function, decreased redox potential, and reduced numbers of presynaptic mitochondria and active zones. We find that neuronal mitochondrial dysfunction stimulates a retrograde signaling response that controls the expression of several hundred nuclear genes. We show that the Drosophila hypoxia inducible factor alpha (HIFα) ortholog Similar (Sima) regulates the expression of several of these retrograde genes, suggesting that Sima mediates mitochondrial retrograde signaling. Remarkably, knockdown of Sima restores neuronal function without affecting the primary mitochondrial defect, demonstrating that mitochondrial retrograde signaling is partly responsible for neuronal dysfunction. Sima knockdown also restores function in a Drosophila model of the mitochondrial disease Leigh syndrome and in a Drosophila model of familial Parkinson’s disease. Thus, mitochondrial retrograde signaling regulates neuronal activity and can be manipulated to enhance neuronal function, despite mitochondrial impairment.

scholarly journals A Metabolic Signature of Mitochondrial Dysfunction Revealed through a Monogenic Form of Leigh Syndrome

Cell Reports ◽  
2015 ◽  
Vol 13 (5) ◽  
pp. 981-989 ◽  
Author(s):  
Julie Thompson Legault ◽  
Laura Strittmatter ◽  
Jessica Tardif ◽  
Rohit Sharma ◽  
Vanessa Tremblay-Vaillancourt ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Leigh Syndrome ◽  
Metabolic Signature ◽  
Monogenic Form

scholarly journals Direct effects of mitochondrial dysfunction on poor bone health in Leigh syndrome

2017 ◽  
Vol 493 (1) ◽  
pp. 207-212 ◽  
Author(s):  
Hiroki Kato ◽  
Xu Han ◽  
Haruyoshi Yamaza ◽  
Keiji Masuda ◽  
Yuta Hirofuji ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Bone Health ◽  
Leigh Syndrome ◽  
Direct Effects

scholarly journals Cell-Permeable Succinate Increases Mitochondrial Membrane Potential and Glycolysis in Leigh Syndrome Patient Fibroblasts

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2255
Author(s):  
Ajibola B. Bakare ◽  
Raj R. Rao ◽  
Shilpa Iyer
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Tricarboxylic Acid Cycle ◽  
Mitochondrial Disorder ◽  
Leigh Syndrome ◽  
High Energy ◽  
Therapeutic Effects ◽  
Organ Systems

Mitochondrial disorders represent a large group of severe genetic disorders mainly impacting organ systems with high energy requirements. Leigh syndrome (LS) is a classic example of a mitochondrial disorder resulting from pathogenic mutations that disrupt oxidative phosphorylation capacities. Currently, evidence-based therapy directed towards treating LS is sparse. Recently, the cell-permeant substrates responsible for regulating the electron transport chain have gained attention as therapeutic agents for mitochondrial diseases. We explored the therapeutic effects of introducing tricarboxylic acid cycle (TCA) intermediate substrate, succinate, as a cell-permeable prodrug NV118, to alleviate some of the mitochondrial dysfunction in LS. The results suggest that a 24-hour treatment with prodrug NV118 elicited an upregulation of glycolysis and mitochondrial membrane potential while inhibiting intracellular reactive oxygen species in LS cells. The results from this study suggest an important role for TCA intermediates for treating mitochondrial dysfunction in LS. We show, here, that NV118 could serve as a therapeutic agent for LS resulting from mutations in mtDNA in complex I and complex V dysfunctions.

scholarly journals Mitochondrial Dysfunction and Calcium Dysregulation in Leigh Syndrome Induced Pluripotent Stem Cell Derived Neurons

2020 ◽  
Vol 21 (9) ◽  
pp. 3191
Author(s):  
Teresa Galera-Monge ◽  
Francisco Zurita-Díaz ◽  
Isaac Canals ◽  
Marita Grønning Hansen ◽  
Laura Rufián-Vázquez ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Disorder ◽  
Induced Pluripotent Stem Cell ◽  
Leigh Syndrome ◽  
In Vitro Models ◽  
Mtdna Mutation ◽  
Electrophysiological Properties ◽  
Induced Pluripotent

Leigh syndrome (LS) is the most frequent infantile mitochondrial disorder (MD) and is characterized by neurodegeneration and astrogliosis in the basal ganglia or the brain stem. At present, there is no cure or treatment for this disease, partly due to scarcity of LS models. Current models generally fail to recapitulate important traits of the disease. Therefore, there is an urgent need to develop new human in vitro models. Establishment of induced pluripotent stem cells (iPSCs) followed by differentiation into neurons is a powerful tool to obtain an in vitro model for LS. Here, we describe the generation and characterization of iPSCs, neural stem cells (NSCs) and iPSC-derived neurons harboring the mtDNA mutation m.13513G>A in heteroplasmy. We have performed mitochondrial characterization, analysis of electrophysiological properties and calcium imaging of LS neurons. Here, we show a clearly compromised oxidative phosphorylation (OXPHOS) function in LS patient neurons. This is also the first report of electrophysiological studies performed on iPSC-derived neurons harboring an mtDNA mutation, which revealed that, in spite of having identical electrical properties, diseased neurons manifested mitochondrial dysfunction together with a diminished calcium buffering capacity. This could lead to an overload of cytoplasmic calcium concentration and the consequent cell death observed in patients. Importantly, our results highlight the importance of calcium homeostasis in LS pathology.

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