Review
Chemistry, Multidisciplinary
Liying Meng, Guanzhao Wu
Summary: Mitochondrial disorders are observed in various human diseases and therapeutic methods for mitochondrial disorders are limited. This review focuses on the latest advances in developing bioactive compounds for treating mitochondrial disease, aiming to provide a broader perspective of fundamental studies that have been carried out to evaluate the effects of small molecules in regulating mitochondrial function.
Review
Medicine, General & Internal
Ignazio Giuseppe Arena, Alessia Pugliese, Sara Volta, Antonio Toscano, Olimpia Musumeci
Summary: Mitochondrial disorders are common, inherited conditions characterized by defects in oxidative phosphorylation caused by mutations in nuclear or mitochondrial genes. Skeletal muscle is typically affected due to its high energy demand. Advances in next-generation sequencing techniques have improved diagnosis and identified new therapeutic targets. An increasing number of mutations have been found to be responsible for mitochondrial disorders.
JOURNAL OF CLINICAL MEDICINE
(2022)
Article
Medicine, Research & Experimental
Mario K. Shammas, Xiaoping Huang, Beverly P. Wu, Evelyn Fessler, Insung Y. Song, Nicholas P. Randolph, Yan Li, Christopher K. E. Bleck, Danielle A. Springer, Carl Fratter, Ines A. Barbosa, Andrew F. Powers, Pedro M. Quiros, Carlos Lopez-Otin, Lucas T. Jae, Joanna Poulton, Derek P. Narendra
Summary: Mitochondrial stress triggers responses in both cellular mitochondria and nucleus. This study focuses on the impact of a mutation in the mitochondrial protein CHCHD10, which causes myopathy. The study finds that the mutated CHCHD10 aggregates in affected tissues, causing toxic stress on the inner mitochondrial membrane. The research also reveals the crucial role of the mitochondrial metalloendopeptidase OMA1 in coordinating stress responses and reshaping the mitochondrial network and proteome.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Review
Biochemistry & Molecular Biology
Ellen A. Goodall, Felix Kraus, J. Wade Harper
Summary: Selective autophagy plays a crucial role in maintaining cellular health by eliminating damaged or superfluous organelles and proteins through specific mechanisms. The attachment of ubiquitin to cargo is a common mechanism for initiating autophagy and a suite of ubiquitin-binding cargo receptors provide selectivity in cargo capture by recruiting the autophagosome initiation machinery. These emerging mechanisms shed light on how selectivity in cargo degradation is achieved in the field of autophagy research.
Review
Cell Biology
Christopher F. Bennett, Pedro Latorre-Muro, Pere Puigserver
Summary: Mitochondrial energetic adaptations are a series of processes that help cells and organisms adapt to changing environments by adjusting the respiratory capacity of mitochondria. These adaptations are regulated by general principles of regulatory biology and are important for maintaining cell survival and adapting to demanding conditions. Failure to execute these adaptations can lead to cell damage, inflammation, and diseases such as metabolic disorders, age-related diseases, and cancer.
NATURE REVIEWS MOLECULAR CELL BIOLOGY
(2022)
Article
Cell Biology
David R. L. Robinson, Daniella H. Hock, Linden Muellner-Wong, Roopasingam Kugapreethan, Boris Reljic, Elliot E. Surgenor, Carlos H. M. Rodrigues, Nikeisha J. Caruana, David A. Stroud
Summary: Mitochondria are complex organelles with diverse proteins that play different roles in the cell. Mutations causing mitochondrial disease can disrupt the assembly of protein complexes and destabilize the interactors, leading to functional defects.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Medicine, Research & Experimental
Nathaniel K. Mullin, Andrew P. Voigt, Miles J. Flamme-Wiese, Xiuying Liu, Megan J. Riker, Katayoun Varzavand, Edwin M. Stone, Budd A. Tucker, Robert F. Mullins
Summary: Variants in the high copy number mitochondrial genome can disrupt organelle function and lead to severe multisystem disease. Heteroplasmy, the uneven distribution of abnormal mtDNA molecules in different cells and tissues, contributes to the wide range of manifestations observed in patients with mitochondrial disease. This study reveals the nonrandom nature of mitochondrial variant distribution in human mitochondrial disease, highlighting its importance for understanding pathogenesis and developing treatments.
Review
Environmental Sciences
Tingting Wu, Zhigang Li, Yongjie Wei
Summary: Mitochondria are double-membraned organelles in eukaryotic cells that determine cell destiny and serve as energy factories. Inhalation of ozone, a highly oxidizing substance in the atmosphere, leads to mitochondrial oxidative stress overload, resulting in the destruction of mitochondrial structure and function and potentially causing various diseases. The specific molecular mechanisms involved in this process require further investigation.
SCIENCE OF THE TOTAL ENVIRONMENT
(2023)
Review
Plant Sciences
Zoltan Molnar, Wogene Solomon, Lamnganbi Mutum, Tibor Janda
Summary: One of the main constraints on agricultural productivity is the low availability of iron in the soil, which affects plant development and physiology. The concentration of iron accessible to plants and microbes in cultivated soil is limited, mainly due to the properties of the soil and the solubility of iron. Plants and soil microorganisms employ active strategies to enhance soil iron availability, such as acidification, chelation, and reduction. Understanding the dynamics of iron in the rhizosphere is crucial for improving plant growth and health.
Article
Genetics & Heredity
Martina Rimoldi, Francesca Magri, Sara Antognozzi, Michela Ripolone, Sabrina Salani, Daniela Piga, Letizia Bertolasi, Simona Zanotti, Patrizia Ciscato, Francesco Fortunato, Maurizio Moggio, Stefania Corti, Giacomo Pietro Comi, Dario Ronchi
Summary: Isolated mitochondrial respiratory chain Complex IV deficiency caused by a variant in the COX assembly factor 8 gene (COA8) was observed in an Italian familial case of mitochondrial myopathy. The patients presented symptoms such as ptosis, muscle weakness, peripheral neuropathy, dysarthria, dysphonia, and cognitive impairment, with muscle biopsy confirming the presence of ragged-red fibers. The identification of a novel homozygous COA8 defect expands the understanding of the clinical spectrum of COA8-related disease, which shows a benign course with intrafamilial clinical variability.
FRONTIERS IN GENETICS
(2023)
Review
Neurosciences
Melanie Gil, Vivian Gama
Summary: Oligodendrocytes are important for the central nervous system's signal transmission and metabolic support. However, the role of mitochondrial-related pathways in oligodendrocyte development is not well understood. Maintaining mitochondrial dynamics is crucial for cellular bioenergetics and the distribution of mitochondria in oligodendrocytes. Understanding the interplay between mitochondrial dynamics, metabolism, and apoptosis will shed light on the mechanisms of oligodendrocyte development. This review provides an overview of oligodendrocyte development and discusses the potential contribution of mitochondrial-mediated mechanisms to oligodendrocyte bioenergetics and development.
JOURNAL OF NEUROSCIENCE RESEARCH
(2023)
Article
Clinical Neurology
Carola Hedberg-Oldfors, Ulrika Lindgren, Kittichate Visuttijai, Daniel Loof, Sara Roos, Christer Thomsen, Anders Oldfors
Summary: Patients with dermatomyositis (DM) have reduced aerobic metabolism and impaired muscle function due to mitochondrial respiratory chain dysfunction. This study found that the deficiency of complexes I and IV is a major cause of the disease, while complex II is unaffected. Depletion of mitochondrial RNA and a decrease in mtDNA copy number in affected muscle regions contribute to the muscle pathology and disturbed aerobic metabolism.
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(2022)
Review
Cell Biology
Jaspreet Kalra
Summary: The association between mitochondrial dysfunction and progression of neurological disorders has gained significant attention. Possible mechanisms involved in these disorders include defects in mitochondrial network dynamics, point mutations, deletions, and interaction of pathogenomic proteins with mitochondria. Shared crosstalk between mitochondrial genetics, defects in mitochondrial oxidative phosphorylation machinery, and reactive oxygen species production might contribute to the progression of these disorders. Exploring and developing therapeutic strategies to correct mitochondrial abnormalities is of great interest.
NEURAL REGENERATION RESEARCH
(2023)
Article
Neurosciences
Nicole J. Van Bergen, Sean Massey, Tegan Stait, Molly Ellery, Boris Reljic, Luke E. Formosa, Anita Quigley, Mirella Dottori, David Thorburn, David A. Stroud, John Christodoulou
Summary: CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental disorder caused by pathogenic variants in the CDKL5 gene, predominantly affecting females and potentially resulting in severe intellectual disability. Research suggests that mitochondrial defects in CDD patients may contribute to the disease pathology, highlighting the importance of investigating mitochondrial dysfunction as a potential focus for targeted treatments for CDD.
NEUROBIOLOGY OF DISEASE
(2021)
Review
Integrative & Complementary Medicine
Yu-hang Jiang, Jia-kai He, Ran Li, Ze-hao Chen, Bao-hui Jia
Summary: Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly, and its pathogenesis remains complex and not fully understood. However, increasing evidence suggests the efficacy of acupuncture in improving the mitochondrial structure and protecting mitochondrial functions in AD. Acupuncture may play a significant role in preventing and treating AD by regulating mitochondrial dynamics, energy metabolism, calcium homeostasis, and apoptosis.
CHINESE JOURNAL OF INTEGRATIVE MEDICINE
(2022)
Article
Immunology
Matthew Hunt, Megan M. McNiff, Amy E. Vincent, Caroline Sabin, Alan Winston, Brendan A. Payne
Summary: This study found that people treated with contemporary antiretroviral therapy have mitochondrial dysfunction in skeletal muscle, exceeding that expected due to age alone. Surprisingly, this dysfunction was not mediated by prior exposure to mitochondrially toxic drugs, suggesting novel mechanisms of mitochondrial dysfunction in individuals receiving contemporary ART.
Article
Medicine, Research & Experimental
Alaa Abouhajar, Lisa Alcock, Theophile Bigirumurame, Penny Bradley, Laura Brown, Ian Campbell, Sylvia Del Din, Julie Faitg, Gavin Falkous, Grainne S. Gorman, Rachel Lakey, Robert McFarland, Jane Newman, Lynn Rochester, Vicky Ryan, Hesther Smith, Alison Steel, Renae J. Stefanetti, Huizhong Su, Robert W. Taylor, Naomi J. P. Thomas, Helen Tuppen, Amy E. Vincent, Charlotte Warren, Gillian Watson
Summary: This study aims to investigate the efficacy of acipimox on skeletal muscle ATP content in patients with mitochondrial disease and myopathy. It is a double-blind, placebo-controlled trial, with a plan to recruit 80 to 120 participants and evaluate the primary and secondary outcomes.
Article
Clinical Neurology
Joanne Trinh, Andrew A. Hicks, Inke R. Koenig, Sylvie Delcambre, Theresa Lueth, Susen Schaake, Kobi Wasner, Jenny Ghelfi, Max Borsche, Carles Vilarino-Gueell, Faycel Hentati, Elisabeth L. Germer, Peter Bauer, Masashi Takanashi, Vladimir Kostic, Anthony E. Lang, Norbert Brueggemann, Peter P. Pramstaller, Irene Pichler, Alex Rajput, Nobutaka Hattori, Matthew J. Farrer, Katja Lohmann, Hansi Weissensteiner, Patrick May, Christine Klein, Anne Gruenewald
Summary: Trinh et al. found that PINK1/PRKN mutations increase the risk of mitochondrial DNA variant accumulation in a dose- and disease-dependent manner. Monoallelic mutation carriers can be distinguished by the level of heteroplasmic mtDNA variants. Biallelic mutations in PINK1/PRKN lead to recessive Parkinson's disease.
Article
Clinical Neurology
Assia Tiane, Melissa Schepers, Rick A. Reijnders, Lieve van Veggel, Sarah Chenine, Ben Rombaut, Emma Dempster, Catherine Verfaillie, Kobi Wasner, Anne Gruenewald, Jos Prickaerts, Ehsan Pishva, Niels Hellings, Daniel van den Hove, Tim Vanmierlo
Summary: In the progressive phase of multiple sclerosis (MS), the differentiation capacity of oligodendrocyte precursor cells (OPCs) is hindered, leading to remyelination failure. Methylation of Id2/Id4 is found to be involved in OPC differentiation and remyelination. This study analyzed the DNA methylation patterns within chronically demyelinated MS lesions and found hypermethylation of genes related to myelination. By altering the DNA methylation state of myelin basic protein (MBP) using epigenetic editing, the differentiation capacity of OPCs and myelination could be manipulated bidirectionally in vitro.
ACTA NEUROPATHOLOGICA
(2023)
Article
Immunology
Melissa Schepers, Dean Paes, Assia Tiane, Ben Rombaut, Elisabeth Piccart, Lieve van Veggel, Pascal Gervois, Esther Wolfs, Ivo Lambrichts, Chiara Brullo, Olga Bruno, Ernesto Fedele, Roberta Ricciarelli, Charles Ffrench-Constant, Marie E. Bechler, Pauline van Schaik, Wia Baron, Evy Lefevere, Kobi Wasner, Anne Grunewald, Catherine Verfaillie, Paulien Baeten, Bieke Broux, Paul Wieringa, Niels Hellings, Jos Prickaerts, Tim Vanmierlo
Summary: Multiple sclerosis (MS) is a chronic autoimmune disease characterized by central nervous system inflammation and demyelination. Current therapies are insufficient in halting or reversing disease progression. This study shows that selective inhibition of phosphodiesterase 4 (PDE4) promotes myelin repair and reduces inflammation. Inhibition of PDE4D enhances (re)myelination, while inhibition of PDE4B exerts anti-inflammatory effects. These findings suggest that gene specific PDE4 inhibitors could be potential therapeutic agents for MS.
BRAIN BEHAVIOR AND IMMUNITY
(2023)
Article
Neurosciences
Sandro L. Pereira, Dajana Grossmann, Sylvie Delcambre, Andreas Hermann, Anne Gruenewald
Summary: Mutations in PRKN gene cause the second most common genetic form of Parkinson's disease (PD) which is a movement disorder increasing due to population aging. PRKN codes for an E3 ubiquitin ligase that acts as a key regulator of mitophagy. Apart from mitochondrial clearance, Parkin is involved in mitochondrial DNA maintenance, biogenesis, apoptosis induction, and modulation of inflammatory pathways. This review summarizes the diverse roles of Parkin in maintaining a healthy mitochondrial pool and discusses the potential personalized therapeutic approaches for PRKN-PD and idiopathic cases.
CURRENT OPINION IN NEUROBIOLOGY
(2023)
Article
Cell & Tissue Engineering
Axel Chemla, Giuseppe Arena, Claudia Saraiva, Clara Berenguer-Escuder, Dajana Grossmann, Anne Grunewald, Christine Klein, Philip Seibler, Jens C. Schwamborn, Rejko Kruger
Summary: In this study, two Parkinson's disease patients' primary skin fibroblasts carrying distinct heterozygous mutations in the RHOT1 gene encoding Miro1 were reprogrammed into induced pluripotent stem cells (iPSCs) using episomal reprogramming. Isogenic gene-corrected lines were generated using CRISPR/Cas9 technology. Both isogenic pairs were comprehensively characterized and quality assured to study the Miro1-related molecular mechanisms underlying neurodegeneration in iPSC-derived neuronal models.
STEM CELL RESEARCH
(2023)
Article
Neurosciences
Maria Paulina Castelo Rueda, Alessandra Zanon, Valentina Gilmozzi, Alexandros A. Lavdas, Athina Raftopoulou, Sylvie Delcambre, Fabiola Del Greco, Christine Klein, Anne Gruenewald, Peter P. Pramstaller, Andrew A. Hicks, Irene Pichler
Summary: Homozygous or compound heterozygous variants in PRKN are causal for PD with highly penetrant symptom expression, while heterozygous variants may predispose to PD with reduced penetrance, through altered mitochondrial function. We generated lymphoblasts and hiPSC-derived neurons from non-manifesting heterozygous PRKN variant carriers and tested them for mitochondrial functionality. We identified molecular phenotypes that might be used to monitor heterozygous PRKN variant carriers during the prodromal phase and to test potential neuroprotective therapies.
NPJ PARKINSONS DISEASE
(2023)
Article
Clinical Neurology
Dajana Grossmann, Nina Malburg, Hannes Glass, Veronika Weeren, Verena Sondermann, Julia F. F. Pfeiffer, Janine Petters, Jan Lukas, Philip Seibler, Christine Klein, Anne Gruenewald, Andreas Hermann
Summary: Recent studies have shown that PINK1 and Parkin play a crucial role in mitochondrial calcium homeostasis and regulation of MERCSs. Using iPSC-derived dopaminergic neurons, researchers found that deficiency in PINK1 or PRKN affects MERCSs dynamics and composition, leading to impaired calcium homeostasis. These findings provide insights into the pathogenesis of PINK1/Parkin-related Parkinson's disease.
MOVEMENT DISORDERS
(2023)
Article
Cell & Tissue Engineering
Axel Chemla, Giuseppe Arena, Gizem Onal, Jonas Walter, Clara Berenguer-Escuder, Dajana Grossmann, Anne Grunewald, Jens C. Schwamborn, Rejko Kruger
Summary: Fibroblasts from two Parkinson's disease patients carrying different mutations in the RHOT1 gene were transformed into iPSCs using RNA-based and episomal reprogramming. Isogenic gene-corrected lines were generated using CRISPR/Cas9 technology. These isogenic pairs will be used to investigate Miro1-related molecular mechanisms in iPSC-derived neuronal models.
STEM CELL RESEARCH
(2023)
Article
Genetics & Heredity
Radwa Sharaf, Dexter X. Jin, John Grady, Christine Napier, Ericka Ebot, Garrett M. Frampton, Lee A. Albacker, David M. Thomas, Meagan Montesion
Summary: In this study, researchers found that tumor cells in sarcomas have a mechanism for limitless replication, which requires the activation of a telomere maintenance mechanism. They also observed that alterations in RAD51B and GID4 genes were more associated with high telomeric content in sarcoma samples compared to alterations in ATRX and DAXX genes. These findings provide research opportunities for understanding the critical pathway in tumorigenesis.
NPJ GENOMIC MEDICINE
(2023)
Article
Neurosciences
Chun Chen, David McDonald, Alasdair Blain, Emily Mossman, Kiera Atkin, Michael F. F. Marusich, Roderick Capaldi, Laura Bone, Anna Smith, Andrew Filby, Daniel Erskine, Oliver Russell, Gavin Hudson, Amy E. E. Vincent, Amy K. K. Reeve
Summary: Using imaging mass cytometry, researchers found a generalized reduction in mitochondrial quality control proteins in dopaminergic neurons from Parkinson's patients. There were also significant differences in protein-protein abundance relationships between PD and disease control tissue. Additionally, abnormal increases in mitochondrial and pathology-related proteins were observed in Parkinson's neurons, suggesting a disturbance in mitochondrial quality control regulation.
NPJ PARKINSONS DISEASE
(2023)
Article
Neurosciences
Milda Aleknonyte-Resch, Joanne Trinh, Hampton Leonard, Sylvie Delcambre, Elsa Leitao, Dongbing Lai, Semra Smajic, Avi Orr-Urtreger, Avner Thaler, Cornelis Blauwendraat, Arunabh B. Sharma, Mary B. Makarious, Jonggeol Jeff Kim, Julie Lake, Pegah Rahmati, Sandra Freitag-Wolf, Philip Seibler, Tatiana B. Foroud, Andrew B. Singleton, Anne Gruenewald, Frank Kaiser, Christine Klein, Michael Krawczak, Astrid Dempfle
Summary: The effects of one genetic factor on Parkinson's disease (PD) risk may be influenced by other genetic factors. This study investigated gene-gene interaction (GxG) in PD using a large dataset of single nucleotide polymorphism (SNP) genotypes. Significant associations between pairwise SNP genotypes were found in PD cases, particularly involving the LRRK2 and SYT10 gene regions. These findings suggest a biologically plausible GxG interaction in PD risk.
NPJ PARKINSONS DISEASE
(2023)
Article
Clinical Neurology
Valeria Di Leo, Conor Lawless, Marie-Pier Roussel, Tiago B. Gomes, Grainne S. Gorman, Oliver M. Russell, Helen A. L. Tuppen, Elise Duchesne, Amy E. Vincent
Summary: This study found that 12-week resistance exercise training can partially rescue mitochondrial dysfunction in DM1 patients. Most patients showed a significant increase in mitochondrial mass, and all patients had a significant increase in protein levels of respiratory chain complexes. Improvements in mitochondrial mass were correlated with strength evaluation.
JOURNAL OF NEUROMUSCULAR DISEASES
(2023)
Review
Biochemistry & Molecular Biology
Valeria Di Leo, Tiago M. Bernardino Gomes, Amy E. Vincent
Summary: Mitochondrial dysfunction in skeletal muscle fibres is common in both healthy aging and neuromuscular diseases, and understanding the impact and adaptation of muscle fibres to this dysfunction is crucial for disease mechanisms and therapeutic interventions. This review provides an overview of current knowledge on interactions between mitochondrial dysfunction and skeletal muscle biology, covering topics such as metabolic remodeling, mitochondrial morphology, mitochondrial turnover, cellular processes, and muscle cell structure and function. The understanding of these interactions is at different stages, with some extensively researched and understood, while others are still in the early stages. The goal of this review is to discuss what is known, highlight what remains unknown, and provide insights into future research directions in this field.
BIOCHEMICAL JOURNAL
(2023)