Review
Medicine, General & Internal
Phepy G. A. Dawod, Jasna Jancic, Ana Marjanovic, Marija Brankovic, Milena Jankovic, Janko Samardzic, Ayman Gamil Anwar Dawod, Ivana Novakovic, Fayda I. Abdel Motaleb, Vladimir Radlovic, Vladimir S. Kostic, Dejan Nikolic
Summary: Mitochondrial encephalomyopathies (MEMP) are complex disorders associated with mitochondrial DNA (mtDNA) mutations. This study conducted genetic analysis on Serbian children and identified known pathogenic mutations in two cases. The research suggests that certain haplogroups may be associated with phenotypic variability in patients with mitochondrial encephalomyopathies.
Article
Anesthesiology
Kira A. Spencer, Michael Mulholland, John Snell, Miranda Howe, Katerina James, Allison R. Hanaford, Philip G. Morgan, Margaret Sedensky, Simon C. Johnson
Summary: The study found that isoflurane is toxic in the Ndufs4(-/-) model of Leigh syndrome. The toxic effects depend on the status of underlying neurologic disease, and can be prevented by the CSF1R inhibitor pexidartinib, and influenced by oxygen concentration in the carrier gas.
BRITISH JOURNAL OF ANAESTHESIA
(2023)
Review
Cell Biology
Massimo Zeviani, Carlo Viscomi
Summary: Mitochondria are vital organelles responsible for generating energy in cells. Mutations in mtDNA or nuclear genes can lead to complex neurological disorders. Understanding these diseases is essential for the field of mitochondrial medicine due to the diverse genetic and phenotypic heterogeneity.
Article
Biochemistry & Molecular Biology
Biyi Chen, Nastaran Daneshgar, Hsiang-Chun Lee, Long-Sheng Song, Dao-Fu Dai
Summary: Mitochondrial oxidative stress plays a role in aging and various cardiovascular diseases. Its involvement in bradyarrhythmia is less understood. In a mouse model of Leigh Syndrome (LS), mitochondrial antioxidant treatment improved bradyarrhythmia and extended lifespan. Increased reactive oxygen species (ROS) in the LS heart were observed and abolished by mitochondrial antioxidant treatment. This study suggests the direct mechanistic roles of mitochondrial ROS in bradyarrhythmia and highlights the potential clinical application of mitochondrial-targeted antioxidants in LS patients.
Article
Biology
Ankit Sabharwal, Mark D. Wishman, Roberto Lopez Cervera, MaKayla R. Serres, Jennifer L. Anderson, Shannon R. Holmberg, Bibekananda Kar, Anthony J. Treichel, Noriko Ichino, Weibin Liu, Jingchun Yang, Yonghe Ding, Yun Deng, Jean M. Lacey, William J. Laxen, Perry R. Loken, Devin Oglesbee, Steven A. Farber, Karl J. Clark, Xiaolei Xu, Stephen C. Ekker, Wenbiao Chen
Summary: The clinical heterogeneity of phenotypes in patients with mitochondrial disorders poses challenges to the understanding of this semi-autonomous organelle. Researchers have created a reversible genetic animal model that replicates certain components of a mitochondrial disorder, including liver dysfunction, highlighting the critical role of the liver in the pathophysiology of the disease.
Article
Cell Biology
Martine Uittenbogaard, Kuntal Sen, Matthew Whitehead, Christine A. Brantner, Yue Wang, Lee-Jun Wong, Andrea Gropman, Anne Chiaramello
Summary: This study aimed to establish the mitochondrial etiology of the proband's progressive neurodegenerative disease suggestive of an atypical Leigh syndrome. Through mitochondrial bioenergetic investigations and whole exome sequencing, three heterozygous nuclear variants associated with Leigh syndrome were identified, providing insights for the development of diagnostic and therapeutic strategies for atypical Leigh syndrome.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Pediatrics
Sungmin Kim, Young-Mock Lee, Kun-Bo Park, Minsu Lee, Hoon Park
Summary: This study investigated the prevalence of hip displacement in patients with mitochondrial disease and found that hip displacement was more common in non-ambulatory patients or those with increased muscle tone. Regular monitoring for hip problems is necessary for non-ambulatory patients with mitochondrial disease.
FRONTIERS IN PEDIATRICS
(2021)
Article
Biology
C. J. Kelly, Reid K. Couch, Vivian T. Ha, Camille M. Bodart, Judy Wu, Sydney Huff, Nicole T. Herrel, Hyunsung D. Kim, Azaad O. Zimmermann, Jessica Shattuck, Yu-Chen Pan, Matt Kaeberlein, Anthony S. Grillo
Summary: Mice lacking Complex I subunit NDUFS4 exhibit mitochondrial dysfunction and the abnormal iron homeostasis may contribute to the progression of Leigh Syndrome and other mitochondrial disorders.
Article
Genetics & Heredity
Anna Ardissone, Claudio Bruno, Daria Diodato, Alice Donati, Daniele Ghezzi, Eleonora Lamantea, Costanza Lamperti, Michelangelo Mancuso, Diego Martinelli, Guido Primiano, Elena Procopio, Anna Rubegni, Filippo Santorelli, Maria Cristina Schiaffino, Serenella Servidei, Flavia Tubili, Enrico Bertini, Isabella Moroni
Summary: Leigh syndrome (LS) is a progressive neurodegenerative disorder associated with mitochondrial dysfunction. This study reviewed data from 122 genetically confirmed LS patients, finding that central nervous system involvement was predominant and often associated with complex I and IV deficiencies. SURF1 mutations were linked to poor prognosis in this large cohort.
ORPHANET JOURNAL OF RARE DISEASES
(2021)
Review
Medicine, General & Internal
Thomas Klopstock, Claudia Priglinger, Ali Yilmaz, Cornelia Kornblum, Felix Distelmaier, Holger Prokisch
Summary: Mitochondrial disorders are highly heterogeneous with a variety of clinical manifestations. A correct diagnosis is crucial for genetic counseling and personalized treatment.
DEUTSCHES ARZTEBLATT INTERNATIONAL
(2021)
Article
Neurosciences
Hayley Christy Miller, Roan Louw, Michelle Mereis, Gerda Venter, John-Drew Boshoff, Liesel Mienie, Mari van Reenen, Marianne Venter, Jeremie Zander Lindeque, Adan Dominguez-Martinez, Albert Quintana, Francois Hendrikus van der Westhuizen
Summary: This study investigated the potential protective effect of metallothioneins (MTs) in a complex I-deficient mouse model, but found that overexpression of MT1 did not lead to improvements in survival, growth, locomotor activity, balance, or motor coordination. Despite subtle reductions in neuroinflammatory markers in certain brain regions, there were no significant differences in metabolomics profiles, gene expression, or ROS levels between the MT1-overexpressing mice and control mice. These findings suggest that MT1 does not protect against impaired motor activity or improve survival in this mitochondrial disease model, possibly due to the unexpected absence of increased oxidative stress and metabolic imbalance. However, tissue-specific observations and differential MT1 expression may indicate a potential tissue- or cell-specific role for MTs in these mice.
MOLECULAR NEUROBIOLOGY
(2021)
Article
Oncology
Jin-Young Yoon, Nastaran Daneshgar, Yi Chu, Biyi Chen, Marco Hefti, Ajit Vikram, Kaikobad Irani, Long-Sheng Song, Charles Brenner, E. Dale Abel, Barry London, Dao-Fu Dai
Summary: This study reveals the mechanistic explanations for cardiac bradyarrhythmia, diastolic dysfunction, and neuronal apoptosis observed in models of Leigh syndrome (LS).
CLINICAL AND TRANSLATIONAL MEDICINE
(2022)
Review
Biochemistry & Molecular Biology
Piervito Lopriore, Fabio Gomes, Vincenzo Montano, Gabriele Siciliano, Michelangelo Mancuso
Summary: Primary mitochondrial diseases are relatively common inborn errors of energy metabolism that typically affect tissues with high energy requirements, including the brain. Epilepsy, affecting >1% of the worldwide population, can be a presenting feature of mitochondrial diseases and poses challenges in treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Clinical Neurology
Sarah L. Stenton, Marketa Tesarova, Natalia L. Sheremet, Claudia Catarino, Valerio Carelli, Elzbieta Ciara, Kathryn Curry, Martin Engvall, Leah R. Fleming, Peter Freisinger, Katarzyna Iwanicka-Pronicka, Elzbieta Jurkiewicz, Thomas Klopstock, Mary K. Koenig, Hana Kolarova, Bohdan Kousal, Tatiana Krylova, Chiara La Morgia, Lenka Noskova, Dorota Piekutowska-Abramczuk, Sam N. Russo, Viktor Stranecky, Iveta Tothova, Frank Traisk, Holger Prokisch
Summary: The study identified 28 previously unreported individuals carrying the DNAJC30 variant, expanding the spectrum of Leber hereditary optic neuropathy and Leigh syndrome. The findings confirmed sex-dependent incomplete penetrance of the homozygous variant and the association of DNAJC30 with Leigh syndrome.
Article
Clinical Neurology
Jingwei Lyu, Yuying Zhao, Na Zhang, Xuebi Xu, Rui Zheng, Wenfei Yu, Wang Xin, Chuanzhu Yan, Kunqian Ji
Summary: Leigh syndrome (LS) is a common mitochondrial encephalopathy disease in infants, and effective therapy is still lacking. A study found that the pan-peroxisome proliferator-activated receptor agonist Bezafibrate (BEZ) has therapeutic effects on a LS animal model, Ndufs4 knockout (KO) mice, improving survival and attenuating disease progression. The study also showed decreased oxidative stress and stunted growth. However, the therapeutic effects of BEZ were not related to mitochondrial biogenesis or enhanced metabolism, but rather to the activation of energy-saving metabolism in mice. The exact mechanism of action still requires further study.
Article
Biology
Julia Stokes, Arielle Freed, Rebecca Bornstein, Kevin N. Su, John Snell, Amanda Pan, Grace X. Sun, Kyung Yeon Park, Sangwook Jung, Hailey Worstman, Brittany M. Johnson, Philip G. Morgan, Margaret M. Sedensky, Simon C. Johnson
Summary: The study shows that volatile anesthetics have unexpected metabolic effects on neonatal mice by depleting b-hydroxybutarate in the blood, while this does not affect adults. The depletion is mediated by citrate accumulation, malonyl-CoA production by acetyl-CoA carboxylase, and inhibition of fatty acid oxidation, leading to reduced metabolic flexibility in adults compared to younger animals.
Article
Anesthesiology
Sangwook Jung, Ernst-Bernhard Kayser, Simon C. Johnson, Li Li, Hailey M. Worstman, Grace X. Sun, Margaret M. Sedensky, Philip G. Morgan
Summary: The study found that tetraethylammonium chloride can effectively reduce anaesthetic-induced neurotoxicity in two different species, indicating therapeutic potential.
BRITISH JOURNAL OF ANAESTHESIA
(2022)
Article
Neurosciences
Rebecca Bornstein, Katerina James, Julia Stokes, Kyung Yeon Park, Ernst-Bernhard Kayser, John Snell, Angela Bard, Yihan Chen, Franck Kalume, Simon C. Johnson
Summary: Genetic mitochondrial diseases are a common cause of inherited metabolic disorders, with Leigh syndrome being the most common clinical presentation in children. While there are no proven therapies for mitochondrial diseases, a ketogenic diet has shown some success in managing mitochondrial epilepsies. mTOR inhibition is being explored as a potential therapeutic target for seizures related to primary mitochondrial dysfunction.
NEUROBIOLOGY OF DISEASE
(2022)
Review
Genetics & Heredity
Dorian M. Cheff, Alysson R. Muotri, Brent R. Stockwell, Edward E. Schmidt, Qitao Ran, Reena V. Kartha, Simon C. Johnson, Plavi Mittal, Elias S. J. Arner, Kristen M. Wigby, Matthew D. Hall, Sanath Kumar Ramesh
Summary: The organization CureGPX4 aims to raise awareness of GPX4-related diseases like SSMD and to support research that could lead to essential therapeutics for patients. They provide an overview of 21 published SSMD cases and additional sequencing data for four previously unpublished individuals to illustrate the genetic component of SSMD and the role of sequencing data in diagnosis. CureGPX4 outlines the steps taken to reach milestones of team creation, disease understanding, drug repurposing, and design of future studies.
ORPHANET JOURNAL OF RARE DISEASES
(2021)
Article
Medicine, Research & Experimental
Julia C. Stokes, Rebecca L. Bornstein, Katerina James, Kyung Yeon Park, Kira A. Spencer, Katie Vo, John C. Snell, Brittany M. Johnson, Philip G. Morgan, Margaret M. Sedensky, Nathan A. Baertsch, Simon C. Johnson
Summary: Leukocyte proliferation plays a crucial role in the pathogenesis of Leigh syndrome, and inhibiting leukocytes can improve disease symptoms and prolong patient survival. This study has important implications for understanding mitochondrial disease mechanisms and developing new therapeutic strategies.
Article
Oncology
Khoa Pham, Allison R. Hanaford, Brad A. Poore, Micah J. Maxwell, Heather Sweeney, Akhila Parthasarathy, Jesse Alt, Rana Rais, Barbara S. Slusher, Charles G. Eberhart, Eric H. Raabe
Summary: The oncogene MYC alters cellular metabolism and its amplification in medulloblastoma leads to distinct metabolic characteristics. Comprehensive metabolic profiling of MYC-amplified medulloblastoma revealed an increased reliance on targetable metabolic pathways. However, metabolism of MYC-amplified cell lines differed from in vivo tumor models, indicating the importance of in vivo metabolic analyses. Understanding the metabolic vulnerabilities of MYC-amplified medulloblastoma may inform the development of targeted therapies.
Review
Genetics & Heredity
Allison R. Hanaford, Yoon-Jae Cho, Hiroyuki Nakai
Summary: Mitochondrial diseases are rare disorders caused by gene mutations and result in defects in mitochondrial function. Effective treatments are currently lacking. Adeno-associated virus (AAV) gene replacement therapy has shown potential for treating mitochondrial diseases.
ORPHANET JOURNAL OF RARE DISEASES
(2022)
Article
Geriatrics & Gerontology
Brenda Gonzalez, Archana Tare, Seungjin Ryu, Simon C. Johnson, Gil Atzmon, Nir Barzilai, Matt Kaeberlein, Yousin Suh
Summary: Mitochondrial dysfunction is a known factor contributing to aging, and this study aims to explore the mechanisms by which mitochondria affect human lifespan. The researchers hypothesize that individuals with exceptional longevity may carry rare variants in nuclear-encoded mitochondrial genes that offer protection against age-related mitochondrial dysfunction. Through their integrated functional genomics study, they identify and prioritize longevity-associated variants, genes, and mitochondrial pathways. The study suggests the functional role of specific mitonuclear genes and pathways in human longevity.
Article
Anesthesiology
Kira A. A. Spencer, Christian B. B. Woods, Hailey M. M. Worstman, Simon C. C. Johnson, Jan-Marino Ramirez, Philip G. G. Morgan, Margaret M. M. Sedensky
Summary: The TREK-1 channel plays a role in the anesthetic sensitivity of cells and its knockout makes mice resistant to volatile anesthetics. The TREK-2 channel does not affect anesthetic sensitivity, and deletion of the TREK channels leads to the involvement of other channels in regulating anesthesia.
Article
Clinical Neurology
Allison R. Hanaford, Asheema Khanna, Vivian Truong, Katerina James, Yihan Chen, Michael Mulholland, Bernhard Kayser, Ryan W. Liao, Margaret Sedensky, Phil Morgan, Nathan Baerchst, Vandana Kalia, Surojit Sarkar, Simon C. Johnson
Summary: Subacute necrotizing encephalopathy, also known as Leigh syndrome (LS), is a common pediatric presentation of genetic mitochondrial disease. LS affects multiple systems and causes severe neurological, metabolic, and musculoskeletal symptoms. Recent research has found that high-dose pexidartinib, a CSF1R inhibitor, can prevent LS CNS lesions and systemic disease. This study focuses on the role of microglia and peripheral macrophages in the pathogenesis of LS.
Article
Anesthesiology
Kira A. Spencer, Michael Mulholland, John Snell, Miranda Howe, Katerina James, Allison R. Hanaford, Philip G. Morgan, Margaret Sedensky, Simon C. Johnson
Summary: The study found that isoflurane is toxic in the Ndufs4(-/-) model of Leigh syndrome. The toxic effects depend on the status of underlying neurologic disease, and can be prevented by the CSF1R inhibitor pexidartinib, and influenced by oxygen concentration in the carrier gas.
BRITISH JOURNAL OF ANAESTHESIA
(2023)
Article
Neurosciences
Rebecca Bornstein, Michael T. Mulholland, Margaret Sedensky, Phil Morgan, Simon C. Johnson
Summary: Mitochondrial dysfunction can lead to altered glutamine metabolism, which plays important roles in neurodegenerative diseases such as Leigh syndrome, MELAS, Alzheimer's, and Parkinson's diseases. Glutamine serves as an alternate carbon source, as well as participating in cellular communication in neurons and astrocytes. Targeting glutamine metabolic pathways may provide therapeutic benefits in these diseases.
MOLECULAR AND CELLULAR NEUROSCIENCE
(2023)
Article
Genetics & Heredity
Sophia Zilber, Kasey Woleben, Simon C. Johnson, Carolina Fischinger Moura de Souza, Danielle Boyce, Kevin Freiert, Courtney Boggs, Souad Messahel, Melinda J. Burnworth, Titilola M. Afolabi, Saima Kayani
Summary: Leigh Syndrome (LS) is a rare genetic neurometabolic disorder that leads to degeneration of the central nervous system. Cure Mito Foundation has established a global patient registry for LS, aiming to provide free access to data for researchers and industry partners, facilitate clinical trial recruitment, and unite international patients and researchers.
ORPHANET JOURNAL OF RARE DISEASES
(2023)