Article
Cell Biology
Sara Capiau, Joel Smet, Boel De Paepe, Yilmaz Yildiz, Mutluay Arslan, Olivier Stevens, Maxime Verschoore, Hedwig Stepman, Sara Seneca, Arnaud Vanlander
Summary: Human mitochondrial disease exhibits significant clinical phenotype variation, even in patients with the same gene defect. This study compares clinical and biochemical data of two patients with the rare pathogenic variant MT-ATP6:m.9035T > C, demonstrating the heterogeneity in disease presentation. Biochemical analysis remains valuable in confirming the genetic diagnosis of mitochondrial disease, particularly in patients with new gene variants or atypical clinical symptoms.
Article
Endocrinology & Metabolism
Ryan H. Peretz, Nicholas Ah Mew, Hilary J. Vernon, Rebecca D. Ganetzky
Summary: Elevated citrulline and C5-OH levels in newborn screening may indicate pathogenic variants in MT-ATP6, which can lead to Leigh syndrome. Early diagnosis and treatment with supplemental citrulline can prevent neurological sequelae. Asymptomatic or paucisymptomatic carriers of MT-ATP6 pathogenic variants in affected families have expanded the clinical spectrum.
MOLECULAR GENETICS AND METABOLISM
(2021)
Review
Clinical Neurology
Kelly N. H. Nudelman, Trever Jackson, Malia Rumbaugh, Ani Eloyan, Marco Abreu, Jeffrey L. Dage, Casey Snoddy, Kelley M. Faber, Tatiana Foroud, Dustin B. Hammers, Alexander Taurone, Maryanne Thangarajah, Paul Aisen, Laurel Beckett, Joel Kramer, Robert Koeppe, Walter A. Kukull, Melissa E. Murray, Arthur W. Toga, Prashanthi Vemuri, Alireza Atri, Gregory S. Day, Ranjan Duara, Neill R. Graff-Radford, Lawrence S. Honig, David T. Jones, Joseph C. Masdeu, Mario Mendez, Erik Musiek, Chiadi U. Onyike, Meghan Riddle, Emily Rogalski, Stephen Salloway, Sharon J. Sha, R. Scott Turner, Thomas S. Wingo, David A. Wolk, Maria C. Carrillo, Bradford C. Dickerson, Gil D. Rabinovici, Liana G. Apostolova
Summary: The Longitudinal Early-onset Alzheimer's Disease Study aims to investigate the genetic causes of early onset cognitive impairment. The study found that the participants had a low frequency of common pathogenic variants.
ALZHEIMERS & DEMENTIA
(2023)
Article
Cell & Tissue Engineering
Tharsini Navaratnarajah, Marlen Bellmann, Annette Seibt, Ruchika Anand, Oezer Degistirici, Roland Meisel, Ertan Mayatepek, Andreas Reichert, Fabian Baertling, Felix Distelmaier
Summary: This study investigated the effects of human mesenchymal stem cells (MSCs) on patients with mitochondrial diseases caused by complex I deficiency. The results showed that co-culturing of complex I-deficient fibroblast with MSCs could lower cellular ROS levels, improve mitochondrial respiration, and normalize the adaptive response. This suggests that MSC-based treatment approaches might be a promising option for patients with mitochondrial DNA-encoded mitochondrial diseases.
STEM CELL RESEARCH & THERAPY
(2022)
Article
Multidisciplinary Sciences
N. L. Barreiro, T. Govezensky, C. Ventura, M. Nunez, P. G. Bolcatto, R. A. Barrio
Summary: Many COVID-19 vaccines have proven to be highly effective in preventing severe disease and reducing infections. However, the uneven distribution of vaccines favors the emergence of new variants, such as the highly transmissible Delta variant, which particularly affects unvaccinated individuals. It is crucial to develop reliable models to analyze the spread of different variants, taking into account vaccination effects and other measures like social behavior. This study presents a stochastic geographical model that fulfills these requirements, allowing for the study of the emergence and dynamics of COVID-19 variants. The model separates disease-related parameters from social behavior and mobility restrictions. Applied to the UK, computer simulations describe the appearance of periodic waves and provide predictions for future vaccination boosters. The model can be applied to other countries as well.
SCIENTIFIC REPORTS
(2022)
Review
Biochemistry & Molecular Biology
Uwe Richter, Robert McFarland, Robert W. Taylor, Sarah J. Pickett
Summary: Mitochondrial diseases are a group of clinically and genetically heterogeneous disorders caused by pathogenic variants in either the nuclear or mitochondrial genome. This review focuses on the most common pathogenic mt-tRNA variants, exploring their clinical manifestations, molecular pathologies, and potential molecular mechanisms of disease. Additionally, the role of mitochondrial-nuclear crosstalk in the manifestation of mt-tRNA-associated disease and the potential for developing treatment options are discussed.
Article
Cell Biology
Emilia Baranowska, Katarzyna Niedzwiecka, Chiranjit Panja, Camille Charles, Alain Dautant, Jaroslaw Poznanski, Jean-Paul di Rago, Deborah Tribouillard-Tanvier, Roza Kucharczyk
Summary: The number of mtDNA variants detected in patients with neurodegenerative diseases is increasing, making it difficult to evaluate their functional consequences and pathogenicity. Saccharomyces cerevisiae provides a convenient model to investigate the functional consequences of these variants. Yeast models of certain MT-ATP6 gene variants showed significant defects in growth and ATP production, indicating their pathogenicity, while yeast models of other variants showed mild or no effect on mitochondrial function, suggesting they do not have the potential to compromise human health.
DISEASE MODELS & MECHANISMS
(2023)
Article
Biochemistry & Molecular Biology
Tiago M. Bernardino Gomes, Yi Shiau Ng, Sarah J. Pickett, Doug M. Turnbull, Amy E. Vincent
Summary: Mitochondrial DNA disorders are recognized as a common cause of inherited metabolic disorders, with a dynamic and tissue-specific pattern that poses challenges to diagnosis and treatment. The complex genetic inheritance of these diseases and the difficulty in finding disease-modifying therapies remain key issues. Advances in techniques such as in vitro fertilization have improved reproductive options, yet further research and exploration are needed.
HUMAN MOLECULAR GENETICS
(2021)
Article
Biochemistry & Molecular Biology
Raquel Moreno-Loshuertos, Nieves Movilla, Joaquin Marco-Brualla, Ruth Soler-Agesta, Patricia Ferreira, Jose Antonio Enriquez, Patricio Fernandez-Silva
Summary: Mitochondrial ATP synthase plays a crucial role in ATP production and is associated with various human diseases. A mouse cell line with the first mt-Atp6 pathological mutation was generated and characterized, showing similarities to human diseases caused by MT-ATP6 mutations. The mutant cells exhibited impaired ATP synthesis, defective OXPHOS activity, and altered mitochondrial function. Additionally, they displayed reduced tumorigenic potential, suggesting a potential protective role of ATP synthase inhibition in certain cancer types.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Genetics & Heredity
Christina G. Tise, Courtney P. Verscaj, Bryce A. Mendelsohn, Jeremy Woods, Chung U. Lee, Gregory M. Enns, Zinandre Stander, Patricia L. Hall, Tina M. Cowan, Kristina P. Cusmano-Ozog
Summary: Low citrulline in newborn screening can be used to identify various mitochondrial diseases. This study found that infants with low citrulline were ultimately diagnosed with MT-ATP6 mitochondrial disease. By comparing with reference data, it is possible to effectively distinguish other types of diseases.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2023)
Article
Obstetrics & Gynecology
K. Okoth, J. Wang, D. Zemedikun, G. N. Thomas, K. Nirantharakumar, N. J. Adderley
Summary: The study shows that women with endometriosis have a higher risk of cardiovascular outcomes compared to those without the condition, particularly in terms of ischemic heart disease, cerebrovascular disease, and heart failure. Although the incidence of endometriosis has decreased over the years, the prevalence of the condition has been on the rise.
BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY
(2021)
Article
Multidisciplinary Sciences
Kelvin Okoth, Anuradhaa Subramanian, Joht Singh Chandan, Nicola J. Adderley, G. Neil Thomas, Krishnarajah Nirantharakumar, Christina Antza
Summary: This study found that women with a history of miscarriage have a higher risk of developing diabetes and hypertension compared to women without a record of miscarriage, indicating a higher cardiometabolic risk in women with miscarriage. Regular monitoring of cardiometabolic health may benefit women with a history of miscarriage.
Article
Genetics & Heredity
Valeria Lo Faro, Ilja M. Nolte, Jacoline B. Ten Brink, Harold Snieder, Nomdo M. Jansonius, Arthur A. Bergen
Summary: This study identified an association between POAG and polymorphisms in the mitochondrial genes MT-ND4 (rs2853496) and MT-CYB (rs35788393), as well as with haplogroup K. These results suggest that mitochondrial genome variations may play a role in the development of POAG, highlighting the need for further genetic and functional studies to better understand the pathophysiological mechanisms involved.
FRONTIERS IN GENETICS
(2021)
Article
Medicine, General & Internal
Tzu-Hsuan Su, Ni-Chung Lee, Chao-Szu Wu, Steven Shinn-Forng Peng, Pi-Chuan Fan
Summary: This article reports a case of a 20-year-old man with episodic weakness and sensorimotor neuropathy, and reveals its association with MT-ATP6 gene mutation.
JOURNAL OF THE FORMOSAN MEDICAL ASSOCIATION
(2022)
Article
Biochemistry & Molecular Biology
Mayyas Saleh Jaweesh, Mohamad Eid Hammadeh, Fatina W. Dahadhah, Mohammad A. Al Smadi, Mazhar Salim Al Zoubi, Manal Issam Abu Alarjah, Houda Amor
Summary: This study analyzed the possible correlations between male sub-fertility and polymorphisms in sperm mitochondrial CO3, ATP6, and ATP8 genes. The results showed that the rs7520428 SNP in MT-CO3 and MT-ATP6 was significantly associated with male sub-fertility, while the studied polymorphic variations in the MT-ATP8 gene did not reveal any significant association.
MOLECULAR BIOLOGY REPORTS
(2022)
Article
Genetics & Heredity
Vicente A. Yepez, Mirjana Gusic, Robert Kopajtich, Christian Mertes, Nicholas H. Smith, Charlotte L. Alston, Rui Ban, Skadi Beblo, Riccardo Berutti, Holger Blessing, Elzbieta Ciara, Felix Distelmaier, Peter Freisinger, Johannes Haeberle, Susan J. Hayflick, Maja Hempel, Yulia S. Itkis, Yoshihito Kishita, Thomas Klopstock, Tatiana D. Krylova, Costanza Lamperti, Dominic Lenz, Christine Makowski, Signe Mosegaard, Michaela F. Mueller, Gerard Munoz-Pujol, Agnieszka Nadel, Akira Ohtake, Yasushi Okazaki, Elena Procopio, Thomas Schwarzmayr, Joel Smet, Christian Staufner, Sarah L. Stenton, Tim M. Strom, Caterina Terrile, Frederic Tort, Rudy Van Coster, Arnaud Vanlander, Matias Wagner, Manting Xu, Fang Fang, Daniele Ghezzi, Johannes A. Mayr, Dorota Piekutowska-Abramczuk, Antonia Ribes, Agnes Roetig, Robert W. Taylor, Saskia B. Wortmann, Kei Murayama, Thomas Meitinger, Julien Gagneur, Holger Prokisch
Summary: The lack of functional evidence hampers variant interpretation, but further sequencing of transcriptomes can help probe gene expression defects. A streamlined experimental and computational process involving RNA-seq analysis of skin fibroblasts led to the establishment of genetic diagnoses for 16% of WES-inconclusive cases, with detection of aberrant gene expression playing a major role in diagnosis, especially in identifying splice-disrupting variants.
Meeting Abstract
Clinical Neurology
Aye Moe, Andrew Schaefer, Grainne Gorman, Yi Shiau Ng
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2022)
Article
Biology
Kelsey A. Nolden, John M. Egner, Jack J. Collier, Oliver M. Russell, Charlotte L. Alston, Megan C. Harwig, Michael E. Widlansky, Souphatta Sasorith, Ines A. Barbosa, Andrew Gl Douglas, Julia Baptista, Mark Walker, Deirdre E. Donnelly, Andrew A. Morris, Hui Jeen Tan, Manju A. Kurian, Kathleen Gorman, Santosh Mordekar, Charu Deshpande, Rajib Samanta, Robert McFarland, R. Blake Hill, Robert W. Taylor, Monika Olahova
Summary: Imbalances in mitochondrial and peroxisomal dynamics contribute to human neurological disorders. This study focused on the role of DRP1 variants in these disorders, revealing that mutations affecting different DRP1 domains lead to developmental delay, seizures, hypotonia, and cardiac complications. The severity of clinical phenotypes correlated with specific variants, with stalk domain variants resulting in more severe symptoms. These mutations impaired protein oligomerisation, DRP1-peroxisomal recruitment, and mitochondrial and peroxisomal hyperfusion. The study also identified a novel pathogenic mechanism, where a specific variant uncouples DRP1 assembly from GTP hydrolysis.
LIFE SCIENCE ALLIANCE
(2022)
Meeting Abstract
Biochemistry & Molecular Biology
Micol Falabella, Luis Carlos Tabara, Olivia V. Poole, Takashi Tatsuta, Shanti Lu, Cathy E. Woodward, Robyn Labrum, Channa Hewamadduma, Erika Fernandez-Vizarra, Thomas Langer, Jan-Willem Taanman, Michael G. Hanna, Julien Prudent, Antonella Spinazzola, Robert D. S. Pitceathly
BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS
(2022)
Article
Clinical Neurology
Chiara Pizzamiglio, Robert D. S. Pitceathly, Michael P. Lunn, Stefen Brady, Fabiola De Marchi, Lucia Galan, Jeannine M. Heckmann, Alejandro Horga, Maria J. Molnar, Acary S. B. Oliveira, Wladimir B. V. R. Pinto, Guido Primiano, Ernestina Santos, Benedikt Schoser, Serenella Servidei, Paulo V. Sgobbi Souza, Vishnu Venugopalan, Michael G. Hanna, Mazen M. Dimachkie, Pedro M. Machado
Summary: Factors associated with the severity of COVID-19 outcomes in people with neuromuscular diseases (NMDs) include age, race/ethnicity, baseline functional status, comorbidities, history of respiratory dysfunction, obesity, number of comorbidities, glucocorticoid treatment, and Guillain-Barre syndrome.
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
Article
Pharmacology & Pharmacy
Marcos R. Chiaratti, Patrick F. Chinnery
Summary: It was previously believed that humans only have one type of mitochondrial DNA (mtDNA), but recent studies have discovered that mixed populations of mtDNA are actually common. The levels of heteroplasmy, or mixed mtDNA, can change significantly during transmission and contribute to mitochondrial diseases and other late onset disorders. While initially thought to be stochastic, the segregation of mtDNA heteroplasmy is now known to be regulated by specific mechanisms. This review provides a synthesis of recent literature on the selection mechanisms for and against mtDNA variants and highlights the gaps in our understanding of this process.
PHARMACOLOGICAL RESEARCH
(2022)
Editorial Material
Clinical Neurology
Katherine R. Schon, Patrick F. Chinnery
PRACTICAL NEUROLOGY
(2023)
Editorial Material
Cell Biology
Yi Shiau Ng, Doug M. Turnbull
Summary: This article discusses the diversity of mitochondrial genetic diseases and presents the study findings on monozygotic twins, revealing the genetic defect of uncoupling ATP production and its clinical manifestations.
Article
Genetics & Heredity
Laura S. Kremer, Lyuba V. Bozhilova, Diana Rubalcava-Gracia, Roberta Filograna, Mamta Upadhyay, Camilla Koolmeister, Patrick F. Chinnery, Nils-Goran Larsson
Summary: In this study, the role of autophagy in germline purifying selection of mtDNA was investigated by mating different autophagy-deficient mouse models with mice carrying a pathogenic tRNA(Ala) gene mutation. The results showed that Bcl2l13 had a significant effect on the selection process, while Ulk1 and Ulk2 had weaker effects, and Parkin had no statistically significant impact. This study provides experimental evidence for the distinct roles of autophagy in germline purifying selection of mtDNA and establishes a framework for future studies on this process.
Article
Genetics & Heredity
Alexander G. Murley, Yu Nie, Zoe Golder, Michael John Keogh, Colin Smith, James W. Ironside, Patrick F. Chinnery
Summary: This study investigated the role of pathologic somatic variants in the PRNP gene in sporadic Creutzfeldt-Jakob disease (sCJD). High-depth amplicon-based sequencing was performed on postmortem brain tissue from sCJD, Alzheimer's disease, and control subjects. The study found somatic PRNP variants in sCJD cases, but their pathogenicity remains uncertain.
NEUROLOGY-GENETICS
(2023)
Review
Biochemistry & Molecular Biology
Elizaveta A. A. Olkhova, Laura A. A. Smith, Carla Bradshaw, Grainne S. Gorman, Daniel Erskine, Yi Shiau Ng
Summary: Mitochondrial diseases are common genetic neurometabolic disorders that currently lack effective therapies. This review discusses various mouse models with transgenic impairments in genes regulating mitochondrial function, focusing on their neurological phenotype and neuropathological features. Most mouse models exhibit ataxia, similar to patients, and share the neuropathological finding of Purkinje neuron loss. However, none of the existing models fully recapitulate the severe neurological phenotypes seen in patients, such as refractory focal seizures and stroke-like episodes. The roles of reactive astrogliosis and microglial reactivity in driving neuropathology, as well as alternative mechanisms of cellular death in neurons during mitochondrial bioenergy crisis, are also discussed.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Clinical Neurology
Pedro M. Machado, Michael P. McDermott, Thomas Blaettler, Claus Sundgreen, Anthony A. Amato, Emma Ciafaloni, Miriam Freimer, Summer B. Gibson, Sarah M. Jones, Todd D. Levine, Thomas E. Lloyd, Tahseen Mozaffar, Aziz Shaibani, Matthew Wicklund, Anders Rosholm, Tim Dehli Carstensen, Karen Bonefeld, Anders Norkaer Jorgensen, Karina Phonekeo, Andrew J. Heim, Laura Herbelin, Richard J. Barohn, Michael G. Hanna, Mazen M. Dimachkie
Summary: Arimoclomol did not show efficacy in individuals with inclusion body myositis compared to placebo, but it had an acceptable safety profile. This study provides valuable data on disease progression for future clinical trial designs in inclusion body myositis.
Correction
Neurosciences
Tracey D. Graves, Robert C. Griggs, Brian N. Bundy, Joanna C. Jen, Robert W. Baloh, Michael G. Hanna
Article
Neurosciences
Tracey D. Graves, Robert C. Griggs, Brian N. Bundy, Joanna C. Jen, Robert W. Baloh, Michael G. Hanna
Summary: Episodic ataxia type 1 (EA1) is a rare autosomal potassium channelopathy that causes intermittent attacks of ataxia in patients. A multi-centre study was conducted to understand the natural history of EA1. The study found that the disability and impairment caused by EA1 did not accumulate significantly over a 2-year period. The quality of life of EA1 patients was lower compared to controls, especially in the physical domain. The study also discovered stable attack duration and frequency in EA1 patients. This prospective study provides valuable data for future clinical trials and outcome measures development.
