Review
Genetics & Heredity
Eduardo Ruiz-Pesini, Julio Montoya, David Pacheu-Grau
Summary: In human mitochondria, mtDNA encodes a small fraction of proteins while the majority are encoded by the nuclear genome and imported into mitochondria through various import machineries. Proper coordination of these molecular pathways is crucial for mitochondrial homeostasis. Studying these pathways is important for understanding and expanding the genetic landscape of mitochondrial diseases.
Article
Biochemistry & Molecular Biology
Chang-Yong Choi, Mai Tram Vo, John Nicholas, Young Bong Choi
Summary: Our study reveals that the mitochondrial translation elongation factor Tu located on the outer membrane of mitochondria can inhibit altered mitochondria-induced apoptosis through its autophagic function. The autophagy-competent TUFM is required for self-dimerization and mitophagy, and its stabilization upon autophagy activation could inhibit caspase-8 activation, providing insights into the regulation of apoptosis by mitophagy.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Biology
Liam P. Coyne, Xiaowen Wang, Jiyao Song, Ebbing de Jong, Karin Schneider, Paul T. Massa, Frank A. Middleton, Thomas Becker, Xin Jie Chen
Summary: This study reveals that amino acid substitutions in a single substrate preprotein can disrupt protein traffic into mitochondria, impair mitochondrial function and cell viability. The mutant Aac2/ANT1 shows extreme toxicity in yeast and leads to muscle disease in mice. These findings highlight the importance of avoiding clogging in mitochondrial carrier proteins for preventing disease.
Review
Biochemistry & Molecular Biology
Megan J. Baker, Jordan J. Crameri, David R. Thorburn, Ann E. Frazier, Diana Stojanovski
Summary: Mitochondrial diseases are a group of metabolic disorders caused by mutations in mitochondrial DNA or nuclear genes. Primary mitochondrial disease is more widely studied than secondary mitochondrial disease. Next generation sequencing techniques have helped identify many novel mitochondrial disease genes, with approximately half linked to secondary mitochondrial disease.
Article
Biochemistry & Molecular Biology
Max-Hinderk Schuler, Alyssa M. English, Tianyao Xiao, Thane J. Campbell, Janet M. Shaw, Adam L. Hughes
Summary: Amino acids are crucial for cellular function, but elevated levels can lead to cellular toxicity. The mitochondrial-derived compartment (MDC) has been identified as a protective mechanism against amino acid stress, promoting amino acid catabolism and maintaining homeostasis through nutrient transporter remodeling.
Article
Multidisciplinary Sciences
Samuel Rout, Silke Oeljeklaus, Abhijith Makki, Jan Tachezy, Bettina Warscheid, Andre Schneider
Summary: The study reveals that the mitochondrial import receptors ATOM46 and ATOM69 of Trypanosoma brucei have different substrate preferences, with ATOM46 favoring hydrophilic proteins and ATOM69 preferring hydrophobic substrates. While ATOM46 mainly uses electrostatic interactions for substrate binding, ATOM69 primarily uses hydrophobic interactions.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Emily Wachoski-Dark, Tian Zhao, Aneal Khan, Timothy E. Shutt, Steven C. Greenway
Summary: There is a unclear mechanistic link between human mitochondrial disorders and the development of cardiomyopathy. Defects in mitochondrial proteostasis, which involves the maintenance of mitochondrial protein homeostasis, can lead to mitochondrial cardiomyopathies. Disruptions in proteostasis can result in mitochondrial dysfunction and impact cardiac function.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Medicine, Research & Experimental
Yanghai Zhang, Zachery R. Gregorich, Yujuan Wang, Camila Urbano Braz, Jibin Zhang, Yang Liu, Peiheng Liu, Jiaxi Shen, Nanyumuzi Aori, Timothy A. Hacker, Henk Granzier, Wei Guo
Summary: Human patients with genetic mutations in RBM20 develop severe dilated cardiomyopathy (DCM). A mouse model with RS domain deletion (Rbm20 & UDelta;RS) showed DCM and mis-splicing of RBM20 target transcripts, indicating the importance of RS domain function for severe DCM. Further studies revealed that DCM-associated mutations in the RS domain facilitate RBM20 nucleocytoplasmic transport and granule assembly, while mutations in the RNA recognition motif do not cause DCM or RBM20 granule formation.
Editorial Material
Endocrinology & Metabolism
Mohamed A. Eldeeb, Andrea Soumbasis, Edward A. Fon
Summary: Given their polyvalent roles, mitochondria face the challenge of continuous exposure to stressors, such as mitochondrial import defects, which result in dysfunction. Recent research has discovered a quality control pathway, dependent on a presequence translocase-associated import motor (PAM) complex, in which misfolded proteins reduce mitochondrial protein import and subsequently trigger mitophagy without loss of mitochondrial membrane potential.
TRENDS IN ENDOCRINOLOGY AND METABOLISM
(2023)
Review
Biochemistry & Molecular Biology
Catherine S. Palmer, Alexander J. Anderson, Diana Stojanovski
Summary: The correct import of proteins into mitochondria is crucial for maintaining cellular homeostasis, and its dysregulation significantly affects cellular signaling pathways and metabolism. Studies on the mammalian mitochondrial import machinery have revealed its importance in the pathogenesis of various diseases.
Article
Biochemistry & Molecular Biology
Naintara Jain, Ridhima Gomkale, Olaf Bernhard, Peter Rehling, Luis Daniel Cruz-Zaragoza
Summary: Mitochondria play a crucial role in cellular energy production and metabolism, and errors in mitochondrial protein import can lead to metabolic disorders. This study establishes a fluorescence-based import assay to analyze protein import into mitochondria, offering the advantage of quantifying import with high sensitivity. The assay can be adapted to a screening-compatible format and used to monitor the assembly of the F1F0 ATP synthase in purified mitochondria.
Article
Biochemistry & Molecular Biology
Tejashree Pradip Waingankar, Patrick D'Silva
Summary: Mitochondrial protein translocation is a complex process regulated by dedicated translocases on the outer and inner membranes. Magmas, a J-like protein subunit of the translocase of the inner membrane 23, can regulate human protein import by forming heterodimers with J-proteins. Additional Magmas variants in humans play a significant role in maximizing protein import under familial-linked pathological conditions.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Qiang Wang, Zeyuan Guan, Liangbo Qi, Jinjin Zhuang, Chen Wang, Sixing Hong, Ling Yan, Yan Wu, Xiaoqian Cao, Jianbo Cao, Junjie Yan, Tingting Zou, Zhu Liu, Delin Zhang, Chuangye Yan, Ping Yin
Summary: Sam37 stabilizes mature Tom40 mainly through electrostatic interactions, facilitating subsequent TOM assembly. These results support the b barrel switching model and offer structural insights into the assembly and release of b barrel complexes.
Review
Biochemistry & Molecular Biology
Juliane J. Hoffmann, Thomas Becker
Summary: Mitochondria import precursor proteins from cytosol through translocase complexes. The phospholipid composition of mitochondrial membranes affects the stability and activity of protein translocases, as well as the rearrangement and distortion of lipid bilayer during protein integration. Phospholipids also play a critical role in respiratory chain activity and membrane potential generation for protein import. The close link between outer membrane protein translocases and lipid trafficking at contact sites further controls mitochondrial biogenesis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Nasif Sayeed, Kiminobu Sugaya
Summary: Mitochondrial dysfunction is a characteristic of neurodegenerative diseases, and the expression level of Tom40 protein is significantly reduced in patients with these diseases. The delivery of Tom40 protein to the brain using engineered exosomes has been found to protect neurons from oxidative stress, suggesting its potential as a novel therapy for neurodegenerative diseases.
Letter
Clinical Neurology
Zune Jansen van Rensburg, Shameemah Abrahams, Devina Chetty, Kathryn Step, Debbie Acker, Carl J. Lombard, Alexis Elbaz, Jonathan Carr, Soraya Bardien
Summary: The incidence of Parkinson's disease is increasing in sub-Saharan Africa, with more Afrikaner Europeans having early-onset PD. More men have PD than women, with men having a younger age at onset (56 years).
MOVEMENT DISORDERS
(2022)
Article
Genetics & Heredity
Nikita Simone Pillay, Owen A. Ross, Alan Christoffels, Soraya Bardien
Summary: The use of next-generation sequencing technologies has aided in the discovery of novel gene loci in familial Parkinson's disease (PD), but the missing heritability of PD has not been resolved significantly. Third-generation sequencing technologies are needed to identify complex genomic rearrangements and new sequence variations. Additionally, studying ancestrally diverse populations and optimizing sequencing and analytic workflows for these populations are critical for exciting new discoveries in the field.
FRONTIERS IN GENETICS
(2022)
Review
Clinical Neurology
Artur Francisco Schumacher-Schuh, Andrei Bieger, Olaitan Okunoye, Kin Ying Mok, Shen-Yang Lim, Soraya Bardien, Azlina Ahmad-Annuar, Bruno Lopes Santos-Lobato, Matheus Zschornack Strelow, Mohamed Salama, Shilpa C. Rao, Yared Zenebe Zewde, Saiesha Dindayal, Jihan Azar, Lingappa Kukkle Prashanth, Roopa Rajan, Alastair J. Noyce, Njideka Okubadejo, Mie Rizig, Suzanne Lesage, Ignacio Fernandez Mata
Summary: This systematic review highlights the significant lack of population diversity in Parkinson's disease genetics research, emphasizing the urgent need for better representation. The Global Parkinson's Genetics Program (GP2) and similar initiatives aim to impact research in underrepresented populations, and the early metrics presented here can be used to measure progress in the field of PD genetics in the future.
MOVEMENT DISORDERS
(2022)
Article
Clinical Neurology
Cloe Domenighetti, Venceslas Douillard, Pierre-Emmanuel Sugier, Ashwin Ashok Kumar Sreelatha, Claudia Schulte, Sandeep Grover, Patrick May, Dheeraj R. Bobbili, Milena Radivojkov-Blagojevic, Peter Lichtner, Andrew B. Singleton, Dena G. Hernandez, Connor Edsall, Pierre-Antoine Gourraud, George D. Mellick, Alexander Zimprich, Walter Pirker, Ekaterina Rogaeva, Anthony E. Lang, Sulev Koks, Pille Taba, Suzanne Lesage, Alexis Brice, Jean-Christophe Corvol, Marie-Christine Chartier-Harlin, Eugenie Mutez, Kathrin Brockmann, Angela B. Deutschlander, Georges M. Hadjigeorgiou, Efthimos Dardiotis, Leonidas Stefanis, Athina Maria Simitsi, Enza Maria Valente, Simona Petrucci, Stefano Duga, Letizia Straniero, Anna Zecchinelli, Gianni Pezzoli, Laura Brighina, Carlo Ferrarese, Grazia Annesi, Andrea Quattrone, Monica Gagliardi, Hirotaka Matsuo, Akiyoshi Nakayama, Nobutaka Hattori, Kenya Nishioka, Sun Ju Chung, Yun Joong Kim, Pierre Kolber, Bart P. C. van de Warrenburg, Bastiaan R. Bloem, Jan Aasly, Mathias Toft, Lasse Pihlstrom, Leonor Correia Guedes, Joaquim J. Ferreira, Soraya Bardien, Jonathan Carr, Eduardo Tolosa, Mario Ezquerra, Pau Pastor, Monica Diez-Fairen, Karin Wirdefeldt, Nancy L. Pedersen, Caroline Ran, Andrea C. Belin, Andreas Puschmann, Emil Ygland Rodstrom, Carl E. Clarke, Karen E. Morrison, Manuela Tan, Dimitri KraincMD, Lena F. Burbulla, Matt J. Farrer, Rejko Kruger, Thomas Gasser, Manu Sharma, Nicolas Vince, Alexis Elbaz
Summary: This study conducted a large-scale independent replication of the interaction between HLA-DRB1 and smoking in Parkinson's disease. The valine at position 11 (V11) in HLA-DRB1 showed the strongest association with PD at the amino acid level. The results suggest an inverse association between genetically predicted smoking initiation and PD, particularly in individuals without the V11 variant. In silico predictions support this interaction pattern by showing the influence of V11 and smoking-induced modifications on binding affinity of alpha-synuclein.
MOVEMENT DISORDERS
(2022)
Article
Clinical Neurology
Amica Corda Muller-Nedebock, Surita Meldau, Carl Lombard, Shameemah Abrahams, Francois Hendrikus van der Westhuizen, Soraya Bardien
Summary: This study investigated whether blood mtDNA-CN levels of African ancestry PD cases would be altered compared to controls. The results showed significantly higher mtDNA-CN in the blood of PD cases.
PARKINSONISM & RELATED DISORDERS
(2022)
Article
Geriatrics & Gerontology
Amica C. Muller-Nedebock, Abigail L. Pfaff, Ilse S. Pienaar, Sulev Koks, Francois H. van der Westhuizen, Joanna L. Elson, Soraya Bardien
Summary: This study investigates the relationship between mitochondrial DNA (mtDNA) variation and Parkinson's disease (PD), focusing on out-of-place variation in African ancestry PD cases. The results show a significant association between out-of-place mtDNA variants and PD risk in African ancestry PD cases.
FRONTIERS IN AGING NEUROSCIENCE
(2022)
Article
Clinical Neurology
Christina Fevga, Christelle Tesson, Ana Carreras Mascaro, Thomas Courtin, Riaan van Coller, Salma Sakka, Federico Ferraro, Nouha Farhat, Soraya Bardien, Mariem Damak, Jonathan Carr, Melanie Ferrien, Valerie Boumeester, Jasmijn Hundscheid, Nicola Grillenzoni, Irini A. Kessissoglou, Demy J. S. Kuipers, Marialuisa Quadri, Jean-Christophe Corvol, Chokri Mhiri, Bassem A. Hassan, Guido J. Breedveld, Suzanne Lesage, Wim Mandemakers, Alexis Brice, Vincenzo Bonifati
Summary: This study identified variants in the PTPA gene associated with early-onset parkinsonism and intellectual disability. These variants lead to impaired activation of the PP2A complex, resulting in neurodegeneration. The Drosophila model further confirmed this mechanism.
Article
Clinical Neurology
Katelyn Cuttler, Dalene de Swardt, Lize Engelbrecht, Jurgen Kriel, Ruben Cloete, Soraya Bardien
Summary: The aim of this study was to investigate the potential role of the translated protein NRXN2 alpha and a specific mutant in Parkinson's disease (PD). Functional studies in an in vitro model showed that cells transfected with the mutant NRXN2 alpha plasmid exhibited decreased cell viability, decreased mitochondrial membrane potential, and increased reactive oxygen species production. These findings suggest that the p.G849D variant may be involved in neuronal death in PD.
JOURNAL OF NEURAL TRANSMISSION
(2022)
Article
Cell Biology
Ambroise Wonkam, Soraya Bardien, Rokhaya Ndiaye Diallo, Amadou Gaye, Mohamed Zahir Alimohamed, Siana Kya, Julie Makani, Guida Landoure, Leon Mutesa, Ghada El-Kamah, Amal Mohamed, Melanie Newport, Scott M. Williams, Michele Ramsay, Victoria Nembaware, Derek Applewhite
Summary: The African Society of Human Genetics aims to provide a platform for scientists in Africa to collaborate on human genetics and genomics research in order to address the public health burden posed by various diseases. They support the Black Lives Matter movement and advocate for an end to the exploitation of African people in genomic research.
MOLECULAR BIOLOGY OF THE CELL
(2022)
Article
Geriatrics & Gerontology
Katelyn Cuttler, Suereta Fortuin, Amica Corda Muller-Nedebock, Mare Vlok, Ruben Cloete, Soraya Bardien
Summary: This study investigated the potential role of NRXN2 alpha in Parkinson's disease, finding that the wild-type NRXN2 alpha may be involved in pathways related to neurodegenerative disorders, while the mutant NRXN2 alpha may affect proteins involved in ribosomal functioning. These findings suggest that translation at the synapse, as well as biological processes related to the ribosome, transcription, and tRNA, may play an important role in the pathobiology of PD.
FRONTIERS IN AGING NEUROSCIENCE
(2022)
Article
Pediatrics
Sharika V. Raga, Jo Madeleine Wilmshurst, Izelle Smuts, Surita Meldau, Soraya Bardien, Maryke Schoonen, Francois Hendrikus van der Westhuizen
Summary: Pediatric neuromuscular diseases are often overlooked and misdiagnosed in Africa, mainly due to socioeconomic barriers, a high burden of diseases, lack of expertise and genetic testing facilities. It is crucial to accurately diagnose these genetic diseases in order for affected children to be eligible for potential treatments. The introduction of a multi-centered research platform aims to address the limited knowledge and improve genetic diagnostic capacities in African populations.
FRONTIERS IN PEDIATRICS
(2022)
Article
Clinical Neurology
Pierre-Emmanuel Sugier, Elise A. Lucotte, Cloe Domenighetti, Matthew H. Law, Mark M. Iles, Kevin Brown, Christopher Amos, James D. McKay, Rayjean J. Hung, Mojgan Karimi, Delphine Bacq-Daian, Anne Boland-Auge, Robert Olaso, Jean-francois Deleuze, Fabienne Lesueur, Evgenia Ostroumova, Ausrele Kesminiene, Florent de Vathaire, Pascal Guenel, Ashwin Ashok Kumar Sreelatha, Claudia Schulte, Sandeep Grover, Patrick May, Dheeraj R. Bobbili, Milena Radivojkov-Blagojevic, Peter Lichtner, Andrew B. Singleton, Dena G. Hernandez, Connor Edsall, George D. Mellick, Alexander Zimprich, Walter Pirker, Ekaterina Rogaeva, Anthony E. Lang, Sulev Koks, Pille Taba, Suzanne Lesage, Alexis Brice, Jean-Christophe Corvol, Marie-Christine Chartier-Harlin, Eugenie Mutez, Kathrin Brockmann, Angela B. Deutschlaender, Georges M. Hadjigeorgiou, Efthimios Dardiotis, Leonidas Stefanis, Athina Maria Simitsi, Enza Maria Valente, Simona Petrucci, Letizia Straniero, Anna Zecchinelli, Gianni Pezzoli, Laura Brighina, Carlo Ferrarese, Grazia Annesi, Andrea Quattrone, Monica Gagliardi, Hirotaka Matsuo, Akiyoshi Nakayama, Nobutaka Hattori, Kenya Nishioka, Sun Ju Chung, Yun Joong Kim, Pierre Kolber, Bart P. C. van de Warrenburg, Bastiaan R. Bloem, Jan Aasly, Mathias Toft, Lasse Pihlstrom, Leonor Correia Guedes, Joaquim J. Ferreira, Soraya Bardien, Jonathan Carr, Eduardo Tolosa, Mario Ezquerra, Pau Pastor, Monica Diez-Fairen, Karin Wirdefeldt, Nancy Pedersen, Caroline Ran, Andrea C. Belin, Andreas Puschmann, Emil Ygland Roedstroem, Carl E. Clarke, Karen E. Morrison, Manuela Tan, Dimitri Krainc, Lena F. Burbulla, Matt J. Farrer, Rejko Kruger, Thomas Gasser, Manu Sharma, Therese Truong, Alexis Elbaz
Summary: By using genome-wide association studies, this study found that Parkinson's disease (PD) is genetically correlated with melanoma and prostate cancer, while it is inversely correlated with ovarian cancer. These findings suggest that pleiotropic genes contribute to the association between PD and specific cancers.
MOVEMENT DISORDERS
(2023)
Article
Clinical Neurology
Rachel Saunders-Pullman, Deborah Raymond, Roberto A. Ortega, Ali Shalash, Emilia Gatto, Mehri Salari, Maggie Markgraf, Roy N. Alcalay, Deborah Mascalzoni, Niccolo E. Mencacci, Vincenzo Bonifati, Marcelo Merello, Sun Ju Chung, Ivana Novakovic, Soraya Bardien, Gian Pal, Anne Hall, Nobutaka Hattori, Timothy Lynch, Avner Thaler, Carolyn M. Sue, Tatiana Foroud, Jennifer Verbrugge, Jeanine Schulze, Lola Cook, Karen Marder, Oksana Suchowersky, Christine Klein, Tatyana Simuni
Summary: This study aims to determine the international landscape of genetic testing in Parkinson's disease (PD) and provide information for future global recommendations. The survey found common barriers such as cost and access to genetic testing and counseling, as well as the need for education on genetic counseling. Region-dependent differences were most notable in Africa, while high-income countries showed heterogeneity, with European nations more likely to have genetic testing covered through insurance than Pan-American and Asian countries. In conclusion, improving education and access to genetic counseling and testing for PD worldwide is highly needed.
MOVEMENT DISORDERS
(2023)
Review
Clinical Neurology
Gian Pal, Lola Cook, Jeanine Schulze, Jennifer Verbrugge, Roy N. Alcalay, Marcelo Merello, Carolyn M. Sue, Soraya Bardien, Vincenzo Bonifati, Sun Ju Chung, Tatiana Foroud, Emilia Gatto, Anne Hall, Nobutaka Hattori, Tim Lynch, Karen Marder, Deborah Mascalzoni, Ivana Novakovic, Avner Thaler, Deborah Raymond, Mehri Salari, Ali Shalash, Oksana Suchowersky, Niccolo E. Mencacci, Tanya Simuni, Rachel Saunders-Pullman, Christine Klein
Summary: Testing for genetic markers in Parkinson's disease is increasingly common, and although there are no proven gene-targeted therapies, clinical trials are underway. However, there is a lack of consensus and guidelines in genetic testing practices, and various gaps and controversies need to be addressed, including appropriateness of testing, variation based on ethnicity, long-term outcomes, and resource needs.
MOVEMENT DISORDERS
(2023)
Article
Neurosciences
Amica C. Mueller-Nedebock, Marieke C. J. Dekker, Matthew J. Farrer, Nobutaka Hattori, Shen-Yang Lim, George D. Mellick, Irena Rektorova, Mohamed Salama, Artur F. S. Schuh, A. Jon Stoessl, Carolyn M. Sue, Ai Huey Tan, Rene L. Vidal, Christine Klein, Soraya Bardien
Summary: The biological basis of Parkinson's disease, a neurodegenerative movement disorder, is still unclear despite being discovered over 200 years ago. This article summarizes the viewpoints of PD experts on the different theories regarding its pathobiology.
NPJ PARKINSONS DISEASE
(2023)