Article
Biology
Andrea Stojakovic, Sergey Trushin, Anthony Sheu, Layla Khalili, Su-Youne Chang, Xing Li, Trace Christensen, Jeffrey L. Salisbury, Rachel E. Geroux, Benjamin Gateno, Padraig J. Flannery, Mrunal Dehankar, Cory C. Funk, Jordan Wilkins, Anna Stepanova, Tara O'Hagan, Alexander Galkin, Jarred Nesbitt, Xiujuan Zhu, Utkarsh Tripathi, Slobodan Macura, Tamar Tchkonia, Tamar Pirtskhalava, James L. Kirkland, Rachel A. Kudgus, Renee A. Schoon, Joel M. Reid, Yu Yamazaki, Takahisa Kanekiyo, Song Zhang, Emirhan Nemutlu, Petras Dzeja, Adam Jaspersen, Ye In Christopher Kwon, Michael K. Lee, Eugenia Trushina
Summary: Partial inhibition of mitochondrial complex I can reduce neurodegeneration and improve key disease phenotypes in a symptomatic mouse model of Alzheimer's disease, including enhancing cognitive function and reducing oxidative stress and inflammation.
COMMUNICATIONS BIOLOGY
(2021)
Article
Biology
Justin A. Bosch, Berrak Ugur, Israel Pichardo-Casas, Jordan Rabasco, Felipe Escobedo, Zhongyuan Zuo, Ben Brown, Susan Celniker, David A. Sinclair, Hugo J. Bellen, Norbert Perrimon
Summary: Naturally produced peptides play important roles in regulating physiology, development, and metabolism. Recent studies suggest that thousands of peptides may be translated from transcripts containing small open-reading frames (smORFs). In Drosophila, two peptides encoded by conserved smORFs, Sloth1 and Sloth2, were found to have similar sequences but non-redundant functions. Loss of either peptide results in animal lethality, reduced neuronal function, impaired mitochondrial function, and neurodegeneration. These peptides are highly expressed in neurons, imported to mitochondria, and regulate mitochondrial complex III assembly.
Article
Clinical Neurology
Michael Zech, Robert Kopajtich, Katja Steinbruecker, Celine Bris, Naig Gueguen, Rene G. Feichtinger, Melanie T. Achleitner, Neslihan Duzkale, Maximilien Perivier, Johannes Koch, Harald Engelhardt, Peter Freisinger, Matias Wagner, Theresa Brunet, Riccardo Berutti, Dmitrii Smirnov, Tharsini Navaratnarajah, Richard J. T. Rodenburg, Lynn S. Pais, Christina Austin-Tse, Melanie O'Leary, Sylvia Boesch, Robert Jech, Somayeh Bakhtiari, Sheng Chih Jin, Friederike Wilbert, Michael C. Kruer, Saskia B. Wortmann, Matthias Eckenweiler, Johannes A. Mayr, Felix Distelmaier, Robert Steinfeld, Juliane Winkelmann, Holger Prokisch
Summary: This study identified novel phenotypes associated with mutations in ATPase subunits, expanding the understanding of ATPase-related diseases. The clinical manifestations of patients with ATPase defects varied, ranging from mild hypotonia to severe epilepsy and developmental delays. Dystonia was a common feature in the affected individuals.
ANNALS OF NEUROLOGY
(2022)
Article
Biotechnology & Applied Microbiology
Pasquale Picone, Gaetana Porcelli, Celeste Caruso Bavisotto, Domenico Nuzzo, Giacoma Galizzi, Pier Luigi San Biagio, Donatella Bulone, Marta Di Carlo
Summary: Synaptosomes have been demonstrated to be a natural vehicle for the delivery of molecules and organelles to neuronal cells, showing potential in replacing damaged mitochondria with healthy ones for treating neuronal mitochondrial dysfunction-related diseases.
JOURNAL OF NANOBIOTECHNOLOGY
(2021)
Review
Cell Biology
Grant C. C. Walters, Yuriy M. M. Usachev
Summary: Mitochondria play essential roles in cellular function, including ATP synthesis, reactive oxygen species production, calcium buffering, and apoptotic signaling. In neurons, calcium buffering is particularly important for regulating various calcium-dependent functions. Recent discoveries of molecular components involved in mitochondrial calcium transport have shed light on the roles of mitochondrial calcium regulation in neuronal function and its implications in neurological diseases. This review discusses the multiple roles of mitochondrial calcium uptake and release mechanisms in normal neuronal function and provides insight into the calcium-dependent mechanisms underlying mitochondrial dysfunction in neurological diseases. The targeting of calcium uptake and release mechanisms could potentially lead to novel therapeutic strategies for these diseases.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Cell Biology
Hezhi Fang, Anran Xie, Miaomiao Du, Xueyun Li, Kaiqiang Yang, Yinxu Fu, Xiangshu Yuan, Runxiao Fan, Weidong Yu, Zhuohua Zhou, Tiantian Sang, Ke Nie, Jin Li, Qiongya Zhao, Zhehui Chen, Yanling Yang, Chaoyang Hong, Jianxin Lyu
Summary: The study revealed that MEGD(H)EL syndrome shares clinical and molecular features with mtDNA depletion syndrome, which is mainly caused by insufficient supply of nucleotides. The supplementation of nucleosides/nucleotides may be an effective therapeutic strategy for MEGD(H)EL syndrome, as it can restore mtDNA content and mitochondrial function.
SCIENCE TRANSLATIONAL MEDICINE
(2022)
Article
Multidisciplinary Sciences
Scott A. Tiscione, Maria Casas, Jonathan D. Horvath, Vincent Lam, Keiko Hino, Daniel S. Ory, L. Fernando Santana, Sergi Simo, Rose E. Dixon, Eamonn J. Dickson
Summary: The study shows that loss-of-function, knockout, or neurodegenerative disease-causing mutations in NPC1 can lead to damaging alterations in the expression and distribution of IP3R1, causing cell death. This process is mediated by SREBP-dependent increases in PS1, with mutants of PS1 recapitulating the Ca2+ phenotypes.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Medicine, General & Internal
Yu Ding, Beibei Gao, Jinyu Huang
Summary: Mitochondrial tRNA mutations in cardiomyopathy are not well understood, but they may affect mitochondrial function and contribute to disease susceptibility. This review provides an overview of tRNA biology and discusses molecular mechanisms underlying mitochondrial dysfunction caused by tRNA mutations.
JOURNAL OF CLINICAL MEDICINE
(2022)
Review
Biochemistry & Molecular Biology
Hilary Y. Liu, Jenna R. Gale, Ian J. Reynolds, John H. Weiss, Elias Aizenman
Summary: Zinc plays essential roles in cellular functions in the brain, but can also induce harmful cascades in neurons, particularly targeting mitochondria. Understanding the mechanisms of zinc-induced mitochondrial defects in neurotoxicity and neurodegeneration may present novel therapeutic targets in clinical settings.
Article
Plant Sciences
Aneta Ivanova, Abi S. Ghifari, Oliver Berkowitz, James Whelan, Monika W. Murcha
Summary: Restoring the function of mitochondrial ATP-dependent metalloprotease FTSH3 can increase the abundance of Complex I and improve plant growth speed. This indicates that the disassembly or degradation of Complex I plays a role in determining its steady-state abundance.
Article
Ophthalmology
Maria I. Avrutsky, Jacqueline M. Lawson, Jade E. Smart, ClaireW. Chen, Carol M. Troy
Summary: This study characterizes ocular pathology in a mouse model of complex I deficiency using noninvasive retinal imaging and visual testing. The results show that the mice develop retinal degeneration at 5 to 7 weeks postnatal, with changes in retinal morphology and impaired visual function. The study demonstrates the utility of noninvasive ocular imaging for investigating retinal pathology associated with complex I deficiency, and the findings have translational relevance to human Leigh syndrome.
TRANSLATIONAL VISION SCIENCE & TECHNOLOGY
(2022)
Article
Multidisciplinary Sciences
Lien B. Lai, Stella M. Lai, Eric S. Szymanski, Mridu Kapur, Edric K. Choi, Hashim M. Al-Hashimi, Susan L. Ackerman, Venkat Gopalan
Summary: n-Tr20 is a neuron-specific, cytoplasmic tRNA isodecoder that affects seizure susceptibility, neuronal excitability, and translation signaling in mice. The C50U substitution in n-Tr20 contributes to neurodegeneration and interacts with Gtpbp1 or Gtpbp2 mutations. Defective tRNA biogenesis may be the basis for neuronal dysfunction in mice with the C50U substitution.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Sean M. Kilbride, Jayne E. Telford, Gavin P. Davey
Summary: The study investigated the effects of inhibiting mitochondrial ETC complexes on the mitochondrial membrane potential and plasma membrane potential in synaptosomal mitochondria. Results showed that reductions in complex I activity had a greater impact on Δψm and Δψp compared to reductions in other ETC complexes.
NEUROCHEMICAL RESEARCH
(2021)
Article
Genetics & Heredity
Irit Hochberg, Leigh A. M. Demain, Julie Richer, Kyle Thompson, Jill E. Urquhart, Alessandro Rea, Waheeda Pagarkar, Agusti Rodriguez-Palmero, Agatha Schluter, Edgard Verdura, Aurora Pujol, Pilar Quijada-Fraile, Albert Amberger, Andrea J. Deutschmann, Sandra Demetz, Meredith Gillespie, Inna A. Belyantseva, Hugh J. McMillan, Melanie Barzik, Glenda M. Beaman, Reeya Motha, Kah Ying Ng, James O'Sullivan, Simon G. Williams, Sanjeev S. Bhaskar, Isabella R. Lawrence, Emma M. Jenkinson, Jessica L. Zambonin, Zeev Blumenfeld, Sergey Yalonetsky, Stephanie Oerum, Walter Rossmanith, Wyatt W. Yue, Johannes Zschocke, Kevin J. Munro, Brendan J. Battersby, Thomas B. Friedman, Robert W. Taylor, Raymond T. O'Keefe, William G. Newman
Summary: Human mitochondrial RNase P processes mitochondrial precursor tRNAs and is composed of three protein subunits. Pathogenic variants in PRORP, one of the subunits, lead to multisystem diseases with symptoms like hearing loss, ovarian insufficiency, and developmental delay. The disease-associated variants result in decreased mitochondrial tRNA processing, indicating that pathogenic variants in all three subunits can cause mitochondrial dysfunction with distinct clinical presentations.
AMERICAN JOURNAL OF HUMAN GENETICS
(2021)
Article
Biochemistry & Molecular Biology
Naoko Nozawa, Marie Noguchi, Kanako Shinno, Taro Saito, Akiko Asada, Takuya Ishii, Kiwamu Takahashi, Masahiro Ishizuka, Kanae Ando
Summary: The use of 5-Aminolevulinic acid hydrochloride and sodium ferrous citrate (5-ALA-HCl + SFC) increases ATP production, enhances the activities of complexes II and IV, and improves metabolic abnormalities and suppresses detrimental phenotypes caused by complex I deficiency.
HUMAN MOLECULAR GENETICS
(2023)
Article
Endocrinology & Metabolism
Kyle Thompson, Jack J. Collier, Ruth I. C. Glasgow, Fiona M. Robertson, Angela Pyle, Emma L. Blakely, Charlotte L. Alston, Monika Olahova, Robert McFarland, Robert W. Taylor
JOURNAL OF INHERITED METABOLIC DISEASE
(2020)
Article
Endocrinology & Metabolism
Nadja Mingirulli, Angela Pyle, Denisa Hathazi, Charlotte L. Alston, Nicolai Kohlschmidt, Gina O'Grady, Leigh Waddell, Frances Evesson, Sandra B. T. Cooper, Christian Turner, Jennifer Duff, Ana Topf, Delia Yubero, Cristina Jou, Andres Nascimento, Carlos Ortez, Angels Garcia-Cazorla, Claudia Gross, Maria O'Callaghan, Saikat Santra, Maryanne A. Preece, Michael Champion, Sergei Korenev, Efsthatia Chronopoulou, Majumdar Anirban, Germaine Pierre, Daniel McArthur, Kyle Thompson, Placido Navas, Antonia Ribes, Frederic Tort, Agatha Schluter, Aurora Pujol, Raquel Montero, Georgia Sarquella, Hanns Lochmueller, Cecilia Jimenez-Mallebrera, Robert W. Taylor, Rafael Artuch, Janbernd Kirschner, Sarah C. Gruenert, Andreas Roos, Rita Horvath
JOURNAL OF INHERITED METABOLIC DISEASE
(2020)
Article
Genetics & Heredity
Charlotte L. Alston, Mike T. Veling, Juliana Heidler, Lucie S. Taylor, Joseph T. Alaimo, Andrew Y. Sung, Langping He, Sila Hopton, Alexander Broomfield, Julija Pavaine, Jullianne Diaz, Eyby Leon, Philipp Wolf, Robert McFarland, Holger Prokisch, Saskia B. Wortmann, Penelope E. Bonnen, Ilka Wittig, David J. Pagliarini, Robert W. Taylor
AMERICAN JOURNAL OF HUMAN GENETICS
(2020)
Letter
Clinical Neurology
Charlotte L. Alston, Emma L. Blakely, Robert McFarland, Robert W. Taylor
JOURNAL OF THE NEUROLOGICAL SCIENCES
(2020)
Review
Endocrinology & Metabolism
Millie Fullerton, Robert McFarland, Robert W. Taylor, Charlotte L. Alston
MOLECULAR GENETICS AND METABOLISM
(2020)
Review
Oncology
Charlotte L. Alston, Sarah L. Stenton, Gavin Hudson, Holger Prokisch, Robert W. Taylor
Summary: Mitochondria play essential roles in metabolism, with mitochondrial diseases clinically diverse and genetically heterogeneous. Genetic diagnosis is crucial for genetic counselling and reproductive options, with next-generation sequencing and multi-omics approaches revolutionizing mitochondrial diagnostics. Patient tissues and integrated multi-omics approach are pivotal for understanding molecular mechanisms in challenging cases.
JOURNAL OF PATHOLOGY
(2021)
Article
Genetics & Heredity
Anne Guimier, Melanie T. Achleitner, Anne Moreau de Bellaing, Matthew Edwards, Loic de Pontual, Kirti Mittal, Kyla E. Dunn, Megan E. Grove, Carolyn J. Tysoe, Clemantine Dimartino, Jessie Cameron, Anil Kanthi, Anju Shukla, Florence van den Broek, Diptendu Chatterjee, Charlotte L. Alston, Charlotte V. Knowles, Laura Brett, Jan A. Till, Tessa Homfray, Paul French, Georgia Spentzou, Noha A. Elserafy, Kate S. Lichkus, Bindu P. Sankaran, Hannah L. Kennedy, Peter M. George, Alexa Kidd, Saskia B. Wortmann, Dianna G. Fisk, Tamara T. Koopmann, Muhammad A. Rafiq, Jason D. Merker, Sumith Parikh, Priyanka Ahimaz, Robert G. Weintraub, Alan S. Ma, Christian Turner, Carolyn J. Ellaway, Liza K. Phillips, David R. Thorburn, Wendy K. Chung, Sajel L. Kana, Ona M. Faye-Petersen, Michelle L. Thompson, Alexandre Janin, Karen McLeod, Ruth McGowan, Robert McFarland, Katta M. Girisha, Deborah J. Morris-Rosendahl, Anna C. E. Hurst, Claire L. S. Turner, Robert M. Hamilton, Robert W. Taylor, Fanny Bajolle, Christopher T. Gordon, Jeanne Amiel, Johannes A. Mayr, Kit Doudney
Summary: Variants in the PPA2 gene lead to heart failure and sudden cardiac arrest at different ages, with significant phenotypic variability within and among families, and some patients may have progressive neurological diseases. Strictly avoiding alcohol intake can prevent cardiac arrest.
GENETICS IN MEDICINE
(2021)
Article
Clinical Neurology
Albert Z. Lim, Yi Shiau Ng, Alasdair Blain, Cecilia Jiminez-Moreno, Charlotte L. Alston, Victoria Nesbitt, Louise Simmons, Saikat Santra, Evangeline Wassmer, Emma L. Blakely, Doug M. Turnbull, Robert W. Taylor, Grainne S. Gorman, Robert McFarland
Summary: This study objectively defined the disease burden and progression of Leigh syndrome among children, revealing that functional decline and extrapyramidal features contribute significantly to disease burden. Predictors of poor outcomes include SURF1 gene variants and bilateral caudate changes on neuroimaging.
ANNALS OF NEUROLOGY
(2022)
Correction
Genetics & Heredity
Anne Guimier, Melanie T. Achleitner, Anne Moreau de Bellaing, Matthew Edwards, Loic de Pontual, Kirti Mittal, Kyla E. Dunn, Megan E. Grove, Carolyn J. Tysoe, Clemantino Dimartino, Jessie Cameron, Anil Kanthi, Anju Shukla, Florence van den Broek, Diptendu Chatterjee, Charlotte L. Alston, Charlotte V. Knowles, Laura Brett, Jan A. Till, Tessa Homfray, Paul French, Georgia Spentzou, Noha A. Elserafy, Kate S. Lichkus, Bindu P. Sankaran, Hannah L. Kennedy, Peter M. George, Alexa Kidd, Saskia B. Wortmann, Dianna G. Fisk, Tamara T. Koopmann, Muhammad A. Rafiq, Jason D. Merker, Sumith Parikh, Priyanka Ahimaz, Robert G. Weintraub, Alan S. Ma, Christian Turner, Carolyn J. Ellaway, Liza K. Phillips, David R. Thorburn, Wendy K. Chung, Sajel L. Kana, Ona M. Faye-Petersen, Michelle L. Thompson, Alexandre Janin, Karen McLeod, Ruth McGowan, Robert McFarland, Katta M. Girisha, Deborah J. Morris-Rosendahl, Anna C. E. Hurst, Claire L. S. Turner, Robert M. Hamilton, Robert W. Taylor, Fanny Bajolle, Christopher T. Gordon, Jeanne Amiel, Johannes A. Mayr, Kit Doudney
GENETICS IN MEDICINE
(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.
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
Environmental Sciences
W. C. Copeland, S. A. Lujan, M. J. Longley, M. H. Humble, C. A. Lavender, A. Burkholder, E. L. Blakely, C. L. Alston, G. S. Gorman, D. M. Turnbull, R. McFarland, R. W. Taylor, T. A. Kunkel
ENVIRONMENTAL AND MOLECULAR MUTAGENESIS
(2020)
Article
Medicine, Research & Experimental
Ahmad Alahmad, Alessia Nasca, Juliana Heidler, Kyle Thompson, Monika Olahova, Andrea Legati, Eleonora Lamantea, Jana Meisterknecht, Manuela Spagnolo, Langping He, Seham Alameer, Fahad Hakami, Abeer Almehdar, Anna Ardissone, Charlotte L. Alston, Robert McFarland, Ilka Wittig, Daniele Ghezzi, Robert W. Taylor
EMBO MOLECULAR MEDICINE
(2020)
Article
Biotechnology & Applied Microbiology
Scott A. Lujan, Matthew J. Longley, Margaret H. Humble, Christopher A. Lavender, Adam Burkholder, Emma L. Blakely, Charlotte L. Alston, Grainne S. Gorman, Doug M. Turnbull, Robert McFarland, Robert W. Taylor, Thomas A. Kunkel, William C. Copeland
Meeting Abstract
Biochemistry & Molecular Biology
E. Mastantuono, B. Repp, C. L. Alston, M. Schiff, T. B. Haack, A. Rotig, A. Ardissone, A. Lombes, C. B. Catarino, D. Diodato, G. Schottmann, J. Poulton, A. Burlina, A. Jonckheere, A. Munnich, D. Ghezzi, D. Rokicki, D. Wellesley, D. Martinelli, E. Lamantea, E. Ostergaard, E. Pronicka, G. Pierre, H. J. Smeets, I. Scurr, I. F. De Coo, I. Moroni, J. Smet, J. A. Mayr, L. De Meirleir, M. Schuelke, M. Zeviani, R. McFarland, S. Seneca, T. Klopstock, T. Meitinger, T. M. Strom, U. Herberg, W. Sperl, M. Nassogne, H. Ling, F. Fang, P. Freisinger, R. Van Coster, R. W. Taylor, J. Haberle, J. Vockley, H. Prokisch, S. Wortmann
EUROPEAN JOURNAL OF HUMAN GENETICS
(2019)