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Raza A, Raina J, Sahu SK, Wadhwa P. Genetic mutations in kinases: a comprehensive review on marketed inhibitors and unexplored targets in Parkinson's disease. Neurol Sci 2025; 46:1509-1524. [PMID: 39760821 DOI: 10.1007/s10072-024-07970-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 12/18/2024] [Indexed: 01/07/2025]
Abstract
This comprehensive review navigates the landscape of genetic mutations in kinases, offering a thorough examination of both marketed inhibitors and unexplored targets in the context of Parkinson's Disease (PD). Although existing treatments for PD primarily center on symptom management, progress in comprehending the molecular foundations of the disease has opened avenues for targeted therapeutic approaches. This review encompasses an in-depth analysis of four key kinases-PINK1, LRRK2, GAK, and PRKRA-revealing that LRRK2 has garnered the most attention with a plethora of marketed inhibitors. However, the study underscores notable gaps in the exploration of inhibitors for PINK1, GAK, and a complete absence for PRKRA. The observed scarcity of inhibitors for these kinases emphasizes a significant area of untapped potential in PD therapeutics. By drawing attention to these unexplored targets, the review highlights the urgent need for focused research and drug development efforts to diversify the therapeutic landscape, potentially providing novel interventions for halting or slowing the progression of PD.
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Affiliation(s)
- Amir Raza
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar- Grand Trunk Rd, Phagwara, Punjab, India
| | - Jeevika Raina
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar- Grand Trunk Rd, Phagwara, Punjab, India
| | - Sanjeev Kumar Sahu
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar- Grand Trunk Rd, Phagwara, Punjab, India
| | - Pankaj Wadhwa
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar- Grand Trunk Rd, Phagwara, Punjab, India.
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2
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Shatalina E, Whitehurst T, Chika Onwordi E, Whittington A, Mansur A, Arumuham A, Reis Marques T, Gunn RN, Natesan S, Nour MM, Rabiner EA, Wall MB, Howes OD. Mitochondria Make You Think: An [18F]BCPP-EF Positron Emission Tomography Study of Mitochondrial Complex I Levels and Brain Activation during Task Switching. BIOLOGICAL PSYCHIATRY. COGNITIVE NEUROSCIENCE AND NEUROIMAGING 2025:S2451-9022(25)00064-3. [PMID: 40010687 DOI: 10.1016/j.bpsc.2025.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 01/29/2025] [Accepted: 02/07/2025] [Indexed: 02/28/2025]
Abstract
BACKGROUND Mitochondrial complex I is the largest enzyme complex in the respiratory chain and can be non-invasively measured using [18F]BCPP-EF positron emission tomography (PET). Neurological conditions associated with mitochondria complex I pathology are also associated with altered blood oxygen level-dependent (BOLD) response and impairments in cognition. This study aims to investigate the relationship between mitochondrial complex I levels, cognitive function, and associated neural activity during task switching in healthy humans. METHODS Cognitively healthy adults (n=23) underwent [18F]BCPP-EF PET scans and functional magnetic resonance imaging (fMRI) while performing a task-switching exercise. Task performance metrics included switch cost and switching accuracy. Data were analysed using linear mixed-effects models and partial least squares regression (PLS-R). RESULTS We found significant positive associations between [18F]BCPP-EF VT and the task-switching fMRI response (β=3.351, SE=1.01, z=3.249, p=0.001). Positive Pearson's correlations between [18F]BCPP-EF VT and the fMRI response were observed in the dorsolateral prefrontal cortex (r=0.61, p=0.0019), insula (r=0.46, p=0.0264) parietal-precuneus (r=0.51, p=0.0139) and anterior cingulate cortex (r=0.45, p=0.0293). [18F]BCPP-EF VT across task-relevant regions was associated with task switching accuracy (PLS-R, R2=0.48, RMSE=0.154, p=0.011) and with switch cost (PLS-R, R2=0.38, RMSE=0.07, p=0.048). CONCLUSIONS Higher mitochondrial complex I levels may underlie an individual's ability to exhibit a stronger BOLD response during task switching and are associated with better task-switching performance. This provides the first evidence linking the BOLD response with mitochondrial complex I and suggests a possible biological mechanism for aberrant BOLD response in conditions associated with mitochondrial complex I dysfunction that should be tested in future studies.
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Affiliation(s)
- Ekaterina Shatalina
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; MRC Laboratory of Medical Science, Imperial College London, London, UK.
| | - Thomas Whitehurst
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; MRC Laboratory of Medical Science, Imperial College London, London, UK; Centre for Psychiatry and Mental Health, Wolfson Institute of Population Health, Queen Mary University of London, London, UK; East London NHS Foundation Trust, London, UK
| | - Ellis Chika Onwordi
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; MRC Laboratory of Medical Science, Imperial College London, London, UK; Centre for Psychiatry and Mental Health, Wolfson Institute of Population Health, Queen Mary University of London, London, UK; East London NHS Foundation Trust, London, UK
| | | | | | - Atheeshaan Arumuham
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; MRC Laboratory of Medical Science, Imperial College London, London, UK; South London and Maudsley NHS Foundation Trust, London, UK
| | - Tiago Reis Marques
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | | | - Sridhar Natesan
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; MRC Laboratory of Medical Science, Imperial College London, London, UK
| | - Matthew M Nour
- Department of Psychiatry, Oxford University, Oxford, UK; Max Planck UCL Centre for Computational Psychiatry and Ageing Research, University College London, London, UK
| | | | - Matthew B Wall
- Invicro, London, UK; Faculty of Medicine, Imperial College London, London, UK
| | - Oliver D Howes
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; MRC Laboratory of Medical Science, Imperial College London, London, UK
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Fei L, Liang Y, Kintscher U, Sigrist SJ. Coupling of mitochondrial state with active zone plasticity in early brain aging. Redox Biol 2025; 79:103454. [PMID: 39642596 PMCID: PMC11666929 DOI: 10.1016/j.redox.2024.103454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 12/02/2024] [Indexed: 12/09/2024] Open
Abstract
Neurodegenerative diseases typically emerge after an extended prodromal period, underscoring the critical importance of initiating interventions during the early stages of brain aging to enhance later resilience. Changes in presynaptic active zone proteins ("PreScale") are considered a dynamic, resilience-enhancing form of plasticity in the process of early, still reversible aging of the Drosophila brain. Aging, however, triggers significant changes not only of synapses but also mitochondria. While the two organelles are spaced in close proximity, likely reflecting a direct functional coupling in regard to ATP and Ca2+ homeostasis, the exact modes of coupling in the aging process remain to understood. We here show that genetic manipulations of mitochondrial functional status, which alters brain oxidative phosphorylation, ATP levels, or the production of reactive oxygen species (ROS), can bidirectionally regulate PreScale during early Drosophila brain aging. Conversely, genetic mimicry of PreScale resulted in decreased oxidative phosphorylation and ATP production, potentially due to reduced mitochondrial calcium (Ca2+) import. Our findings indicate the existence of a positive feedback loop where mitochondrial functional state and PreScale are reciprocally coupled to optimize protection during the early stages of brain aging.
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Affiliation(s)
- Lu Fei
- Institute for Biology/Genetics, Freie Universität Berlin, 14195, Berlin, Germany
| | - Yongtian Liang
- Institute for Biology/Genetics, Freie Universität Berlin, 14195, Berlin, Germany; NeuroCure Cluster of Excellence, Charité Universitätmedizin Berlin, 10117, Berlin, Germany
| | - Ulrich Kintscher
- Institute of Pharmacology, Center for Cardiovascular Research, Charité Universitätmedizin Berlin, 10115, Berlin, Germany; German Centre for Cardiovascular Research (DZHK), partner site Berlin, 10117, Berlin, Germany
| | - Stephan J Sigrist
- Institute for Biology/Genetics, Freie Universität Berlin, 14195, Berlin, Germany; NeuroCure Cluster of Excellence, Charité Universitätmedizin Berlin, 10117, Berlin, Germany.
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4
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Jara C, Torres AK, Park-Kang HS, Sandoval L, Retamal C, Gonzalez A, Ricca M, Valenzuela S, Murphy MP, Inestrosa NC, Tapia-Rojas C. Curcumin Improves Hippocampal Cell Bioenergetics, Redox and Inflammatory Markers, and Synaptic Proteins, Regulating Mitochondrial Calcium Homeostasis. Neurotox Res 2025; 43:3. [PMID: 39775210 DOI: 10.1007/s12640-024-00726-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 08/09/2024] [Accepted: 12/21/2024] [Indexed: 01/30/2025]
Abstract
Mitochondria produces energy through oxidative phosphorylation (OXPHOS), maintaining calcium homeostasis, survival/death cell signaling mechanisms, and redox balance. These mitochondrial functions are especially critical for neurons. The hippocampus is crucial for memory formation in the brain, which is a process with high mitochondrial function demand. Loss of hippocampal function in aging is related to neuronal damage, where mitochondrial impairment is critical. Synaptic and mitochondrial dysfunction are early events in aging; both are regulated reciprocally and contribute to age-associated memory loss together. We previously showed that prolonged treatment with Curcumin or Mitoquinone (MitoQ) improves mitochondrial functions in aged mice, exerting similar neuroprotective effects. Curcumin has been described as an anti-inflammatory and antioxidant compound, and MitoQ is a potent antioxidant directly targeting mitochondria; however, whether Curcumin exerts a direct impact on the mitochondria is unclear. In this work, we study whether Curcumin could have a mechanism similar to MitoQ targeting the mitochondria. We utilized hippocampal slices of 4-6-month-old C57BL6 mice to assess the cellular changes induced by acute Curcumin treatment ex-vivo compared to MitoQ. Our results strongly suggest that both compounds improve the synaptic structure, oxidative state, and energy production in the hippocampus. Nevertheless, Curcumin and MitoQ modify mitochondrial function differently; MitoQ improves the mitochondrial bioenergetics state, reducing ROS production and increasing ATP generation. In contrast, Curcumin reduces mitochondrial calcium levels and prevents calcium overload related to mitochondrial swelling. Thus, Curcumin is described as a new regulator of mitochondrial calcium homeostasis and could be used in pathological events involving calcium deregulation and excitotoxicity, such as aging and neurodegenerative diseases.
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Affiliation(s)
- Claudia Jara
- Laboratory of Neurobiology of Aging, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Avenida del Valle Norte 725, Huechuraba, Santiago, 8580702, Chile
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Lota 2465, Santiago, 7510157, Chile
| | - Angie K Torres
- Laboratory of Neurobiology of Aging, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Avenida del Valle Norte 725, Huechuraba, Santiago, 8580702, Chile
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Lota 2465, Santiago, 7510157, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Escuela de Medicina, Universidad de Magallanes, Punta Arenas, Avenida Los Flamencos, Punta Arenas, 01364, Chile
| | - Han S Park-Kang
- Laboratory of Neurobiology of Aging, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Avenida del Valle Norte 725, Huechuraba, Santiago, 8580702, Chile
| | - Lisette Sandoval
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Lota 2465, Santiago, 7510157, Chile
| | - Claudio Retamal
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Lota 2465, Santiago, 7510157, Chile
| | - Alfonso Gonzalez
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Avenida del Valle Norte 725, Huechuraba, Santiago, 8580702, Chile
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Lota 2465, Santiago, 7510157, Chile
| | - Micaela Ricca
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Lota 2465, Santiago, 7510157, Chile
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Avenida del Valle Norte 725, Huechuraba, Santiago, 8580702, Chile
| | - Sebastián Valenzuela
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Lota 2465, Santiago, 7510157, Chile
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Avenida del Valle Norte 725, Huechuraba, Santiago, 8580702, Chile
| | - Michael P Murphy
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Nibaldo C Inestrosa
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Escuela de Medicina, Universidad de Magallanes, Punta Arenas, Avenida Los Flamencos, Punta Arenas, 01364, Chile
| | - Cheril Tapia-Rojas
- Laboratory of Neurobiology of Aging, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Avenida del Valle Norte 725, Huechuraba, Santiago, 8580702, Chile.
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Lota 2465, Santiago, 7510157, Chile.
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Kodavati M, Hegde ML. A Commentary on Mitochondrial Dysfunction and Compromised DNA Repair in Neurodegeneration: The Emerging Role of FUS in ALS. Neurosci Insights 2024; 19:26331055241305151. [PMID: 39679063 PMCID: PMC11645713 DOI: 10.1177/26331055241305151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 11/20/2024] [Indexed: 12/17/2024] Open
Abstract
Mitochondrial dysfunction plays a pivotal role in the progression of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's, and Parkinson's disease. Recent discoveries have highlighted the involvement of DNA damage and repair processes, particularly mitochondrial DNA (mtDNA) damage, in these conditions. This commentary reflects on our recent findings, demonstrating the RNA/DNA binding protein fused in sarcoma (FUS)'s crucial role in maintaining mtDNA integrity through interactions with mitochondrial DNA ligase IIIα (mtLig3). Our studies provide direct evidence of increased mtDNA damage in ALS-linked FUS mutant cells, emphasizing the potential of targeting DNA repair pathways to mitigate neurodegeneration. Furthermore, the restoration of mitochondrial function through targeted expression of human DNA ligase 1 (Lig1) in FUS mutant models showcases the therapeutic promise of DNA repair mechanisms in neurodegenerative diseases. These insights offer new molecular understanding and open up future avenues for therapeutic interventions, particularly in FUS-associated ALS and related disorders.
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Affiliation(s)
- Manohar Kodavati
- Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA
| | - Muralidhar L Hegde
- Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA
- Department of Neurosurgery, Weill Medical College, New York, NY, USA
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6
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Thompson JR, Nelson ED, Tippani M, Ramnauth AD, Divecha HR, Miller RA, Eagles NJ, Pattie EA, Kwon SH, Bach SV, Kaipa UM, Yao J, Hou C, Kleinman JE, Collado-Torres L, Han S, Maynard KR, Hyde TM, Martinowich K, Page SC, Hicks SC. An integrated single-nucleus and spatial transcriptomics atlas reveals the molecular landscape of the human hippocampus. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.26.590643. [PMID: 38712198 PMCID: PMC11071618 DOI: 10.1101/2024.04.26.590643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2024]
Abstract
The hippocampus contains many unique cell types, which serve the structure's specialized functions, including learning, memory and cognition. These cells have distinct spatial organization, morphology, physiology, and connectivity, highlighting the importance of transcriptome-wide profiling strategies that retain cytoarchitectural organization. Here, we generated spatially-resolved transcriptomics (SRT) and single-nucleus RNA-sequencing (snRNA-seq) data from adjacent tissue sections of the anterior human hippocampus in ten adult neurotypical donors to define molecular profiles for hippocampal cell types and spatial domains. Using non-negative matrix factorization (NMF) and label transfer, we integrated these data by defining gene expression patterns within the snRNA-seq data and inferring their expression in the SRT data. We identified NMF patterns that captured transcriptional variation across neuronal cell types and indicated that the response of excitatory and inhibitory postsynaptic specializations were prioritized in different SRT spatial domains. We used the NMF and label transfer approach to leverage existing rodent datasets, identifying patterns of activity-dependent transcription and subpopulations of dentate gyrus granule cells in our SRT dataset that may be predisposed to participate in learning and memory ensembles. Finally, we characterized the spatial organization of NMF patterns corresponding to non-cornu ammonis pyramidal neurons and identified snRNA-seq clusters mapping to distinct regions of the retrohippocampus, to three subiculum layers, and to a population of presubiculum neurons. To make this comprehensive molecular atlas accessible to the scientific community, both raw and processed data are freely available, including through interactive web applications.
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Affiliation(s)
- Jacqueline R. Thompson
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Erik D. Nelson
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
- Cellular and Molecular Medicine Graduate Program, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Madhavi Tippani
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
| | - Anthony D. Ramnauth
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Heena R. Divecha
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
| | - Ryan A. Miller
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
| | - Nicholas J. Eagles
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
| | - Elizabeth A. Pattie
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
| | - Sang Ho Kwon
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Biochemistry, Cellular, and Molecular Biology Graduate Program, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Svitlana V. Bach
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Uma M. Kaipa
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
| | - Jianing Yao
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Christine Hou
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Joel E. Kleinman
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Leonardo Collado-Torres
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
| | - Shizhong Han
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Department of Genetic Medicine, Johns Hopkins School of Medicine, MD, USA
| | - Kristen R. Maynard
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Thomas M. Hyde
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Keri Martinowich
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Department of Genetic Medicine, Johns Hopkins School of Medicine, MD, USA
- Johns Hopkins Kavli Neuroscience Discovery Institute, Baltimore, MD, USA
| | - Stephanie C. Page
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Stephanie C. Hicks
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
- Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA
- Malone Center for Engineering in Healthcare, Johns Hopkins University, Baltimore, MD, USA
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Motanova E, Pirazzini M, Negro S, Rossetto O, Narici M. Impact of ageing and disuse on neuromuscular junction and mitochondrial function and morphology: Current evidence and controversies. Ageing Res Rev 2024; 102:102586. [PMID: 39557298 DOI: 10.1016/j.arr.2024.102586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 11/01/2024] [Accepted: 11/12/2024] [Indexed: 11/20/2024]
Abstract
Inactivity and ageing can have a detrimental impact on skeletal muscle and the neuromuscular junction (NMJ). Decreased physical activity results in muscle atrophy, impaired mitochondrial function, and NMJ instability. Ageing is associated with a progressive decrease in muscle mass, deterioration of mitochondrial function in the motor axon terminals and in myofibres, NMJ instability and loss of motor units. Focusing on the impact of inactivity and ageing, this review examines the consequences on NMJ stability and the role of mitochondrial dysfunction, delving into their complex relationship with ageing and disuse. Evidence suggests that mitochondrial dysfunction can be a pathogenic driver for NMJ alterations, with studies revealing the role of mitochondrial defects in motor neuron degeneration and NMJ instability. Two perspectives behind NMJ instability are discussed: one is that mitochondrial dysfunction in skeletal muscle triggers NMJ deterioration, the other envisages dysfunction of motor terminal mitochondria as a primary contributor to NMJ instability. While evidence from these studies supports both perspectives on the relationship between NMJ dysfunction and mitochondrial impairment, gaps persist in the understanding of how mitochondrial dysfunction can cause NMJ deterioration. Further research, both in humans and in animal models, is essential for unravelling the mechanisms and potential interventions for age- and inactivity-related neuromuscular and mitochondrial alterations.
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Affiliation(s)
- Evgeniia Motanova
- Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy.
| | - Marco Pirazzini
- Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy; CIR-MYO Myology Center, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy
| | - Samuele Negro
- Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy; CIR-MYO Myology Center, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy
| | - Ornella Rossetto
- Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy; CIR-MYO Myology Center, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy; Institute of Neuroscience, National Research Council, Via Ugo Bassi 58/B, Padova 35131, Italy
| | - Marco Narici
- Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy; CIR-MYO Myology Center, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy
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8
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Cicali KA, Tapia-Rojas C. Synaptic mitochondria: A crucial factor in the aged hippocampus. Ageing Res Rev 2024; 101:102524. [PMID: 39369797 DOI: 10.1016/j.arr.2024.102524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 09/25/2024] [Accepted: 09/25/2024] [Indexed: 10/08/2024]
Abstract
Aging is a multifaceted biological process characterized by progressive molecular and cellular damage accumulation. The brain hippocampus undergoes functional deterioration with age, caused by cellular deficits, decreased synaptic communication, and neuronal death, ultimately leading to memory impairment. One of the factors contributing to this dysfunction is the loss of mitochondrial function. In neurons, mitochondria are categorized into synaptic and non-synaptic pools based on their location. Synaptic mitochondria, situated at the synapses, play a crucial role in maintaining neuronal function and synaptic plasticity, whereas non-synaptic mitochondria are distributed throughout other neuronal compartments, supporting overall cellular metabolism and energy supply. The proper function of synaptic mitochondria is essential for synaptic transmission as they provide the energy required and regulate calcium homeostasis at the communication sites between neurons. Maintaining the structure and functionality of synaptic mitochondria involves intricate processes, including mitochondrial dynamics such as fission, fusion, transport, and quality control mechanisms. These processes ensure that mitochondria remain functional, replace damaged organelles, and sustain cellular homeostasis at synapses. Notably, deficiencies in these mechanisms have been increasingly associated with aging and the onset of age-related neurodegenerative diseases. Synaptic mitochondria from the hippocampus are particularly vulnerable to age-related changes, including alterations in morphology and a decline in functionality, which significantly contribute to decreased synaptic activity during aging. This review comprehensively explores the critical roles that mitochondrial dynamics and quality control mechanisms play in preserving synaptic activity and neuronal function. It emphasizes the emerging evidence linking the deterioration of synaptic mitochondria to the aging process and the development of neurodegenerative diseases, highlighting the importance of these organelles from hippocampal neurons as potential therapeutic targets for mitigating cognitive decline and synaptic degeneration associated with aging. The novelty of this review lies in its focus on the unique vulnerability of hippocampal synaptic mitochondria to aging, underscoring their importance in maintaining brain function across the lifespan.
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Affiliation(s)
- Karina A Cicali
- Laboratory of Neurobiology of Aging, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Huechuraba, Santiago 8580702, Chile; Facultad de Medicina y Ciencia, Universidad San Sebastián, Lota 2465, Santiago 7510157, Chile
| | - Cheril Tapia-Rojas
- Laboratory of Neurobiology of Aging, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Huechuraba, Santiago 8580702, Chile; Facultad de Medicina y Ciencia, Universidad San Sebastián, Lota 2465, Santiago 7510157, Chile.
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9
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Wigstrom TP, Roytman S, Bohnen JLB, Paalanen RR, Griggs AM, Vangel R, Barr J, Albin R, Kanel P, Bohnen NI. Impaired mitochondrial function in bipolar disorder and alcohol use disorder: a case study using 18F-BCPP-EF PET imaging of mitochondrial Complex I. PSYCHORADIOLOGY 2024; 4:kkae014. [PMID: 39399447 PMCID: PMC11467810 DOI: 10.1093/psyrad/kkae014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/17/2024] [Accepted: 09/02/2024] [Indexed: 10/15/2024]
Abstract
Background With bipolar disorder (BD) having a lifetime prevalence of 4.4% and a significant portion of patients being chronically burdened by symptoms, there has been an increased focus on uncovering new targets for intervention in BD. One area that has shown early promise is the mitochondrial hypothesis. However, at the time of publication no studies have utilized positron emission tomography (PET) imaging to assess mitochondrial function in the setting of BD. Case Presentation Our participant is a 58 year-old male with a past medical history notable for alcohol use disorder and BD (unspecified type) who underwent PET imaging with the mitochondrial complex I PET ligand 18F-BCPP-EF. The resulting images demonstrated significant overlap between areas of dysfunction identified with the 18F-BCPP-EF PET ligand and prior functional magnetic resonance imaging (MRI) techniques in the setting of BD. That overlap was seen in both affective and cognitive circuits, with mitochondrial dysfunction in the fronto-limbic, ventral affective, and dorsal cognitive circuits showing particularly significant differences. Conclusions Despite mounting evidence implicating mitochondria in BD, this study represents the first PET imaging study to investigate this mechanistic connection. There were key limitations in the form of comorbid alcohol use disorder, limited statistical power inherent to a case study, no sex matched controls, and the absence of a comprehensive psychiatric history. However, even with these limitations in mind, the significant overlap between dysfunction previously demonstrated on functional MRI and this imaging provides compelling preliminary evidence that strengthens the mechanistic link between mitochondrial dysfunction and BD.
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Affiliation(s)
- Travis P Wigstrom
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
- University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Stiven Roytman
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jeffrey L B Bohnen
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
- University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Rebecca R Paalanen
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Alexis M Griggs
- University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Robert Vangel
- University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Jaimie Barr
- University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Roger Albin
- University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Prabesh Kanel
- University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Nicolaas I Bohnen
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
- University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Neurology Service and GRECC, VA Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA
- Morris K. Udall Center of Excellence for Parkinson's Disease Research, University of Michigan, Ann Arbor, MI 48109, USA
- Parkinson's Foundation Research Center of Excellence, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA
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10
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Karl MT, Kim YD, Rajendran K, Manger PR, Sherwood CC. Invariance of Mitochondria and Synapses in the Primary Visual Cortex of Mammals Provides Insight Into Energetics and Function. J Comp Neurol 2024; 532:e25669. [PMID: 39291629 PMCID: PMC11412485 DOI: 10.1002/cne.25669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 08/16/2024] [Accepted: 08/30/2024] [Indexed: 09/19/2024]
Abstract
The cerebral cortex accounts for substantial energy expenditure, primarily driven by the metabolic demands of synaptic signaling. Mitochondria, the organelles responsible for generating cellular energy, play a crucial role in this process. We investigated ultrastructural characteristics of the primary visual cortex in 18 phylogenetically diverse mammals, spanning a broad range of brain sizes from mouse to elephant. Our findings reveal remarkable uniformity in synapse density, postsynaptic density (PSD) length, and mitochondria density, indicating functional and metabolic constraints that maintain these fundamental features. Notably, we observed an average of 1.9 mitochondria per synapse across mammalian species. When considered together with the trend of decreasing neuron density with larger brain size, we find that brain enlargement in mammals is characterized by increasing proportions of synapses and mitochondria per cortical neuron. These results shed light on the adaptive mechanisms and metabolic dynamics that govern cortical ultrastructure across mammals.
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Affiliation(s)
- Molly T Karl
- Department of Anthropology and Center for the Advanced Study of Human Paleobiology, The George Washington University, Washington, District of Columbia, USA
- Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, The George Washington University, Washington, District of Columbia, USA
| | - Young Do Kim
- Department of Anthropology and Center for the Advanced Study of Human Paleobiology, The George Washington University, Washington, District of Columbia, USA
| | - Kavita Rajendran
- Department of Anthropology and Center for the Advanced Study of Human Paleobiology, The George Washington University, Washington, District of Columbia, USA
| | - Paul R Manger
- Faculty of Health Sciences, School of Anatomical Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Chet C Sherwood
- Department of Anthropology and Center for the Advanced Study of Human Paleobiology, The George Washington University, Washington, District of Columbia, USA
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11
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Tait C, Chicco AJ, Naug D. Brain energy metabolism as an underlying basis of slow and fast cognitive phenotypes in honeybees. J Exp Biol 2024; 227:jeb247835. [PMID: 39092671 PMCID: PMC11418170 DOI: 10.1242/jeb.247835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 07/19/2024] [Indexed: 08/04/2024]
Abstract
In the context of slow-fast behavioral variation, fast individuals are hypothesized to be those who prioritize speed over accuracy while slow individuals are those which do the opposite. Since energy metabolism is a critical component of neural and cognitive functioning, this predicts such differences in cognitive style to be reflected at the level of the brain. We tested this idea in honeybees by first classifying individuals into slow and fast cognitive phenotypes based on a learning assay and then measuring their brain respiration with high-resolution respirometry. Our results broadly show that inter-individual differences in cognition are reflected in differences in brain mass and accompanying energy use at the level of the brain and the whole animal. Larger brains had lower mass-specific energy usage and bees with larger brains had a higher metabolic rate. These differences in brain respiration and brain mass were, in turn, associated with cognitive differences, such that bees with larger brains were fast cognitive phenotypes whereas those with smaller brains were slow cognitive phenotypes. We discuss these results in the context of the role of energy in brain functioning and slow-fast decision making and speed accuracy trade-off.
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Affiliation(s)
- Catherine Tait
- Department of Biology, Colorado State University, Fort Collins, CO 80523, USA
| | - Adam J. Chicco
- Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
| | - Dhruba Naug
- Department of Biology, Colorado State University, Fort Collins, CO 80523, USA
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12
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Sayehmiri F, Motamedi F, Batool Z, Naderi N, Shaerzadeh F, Zoghi A, Rezaei O, Khodagholi F, Pourbadie HG. Mitochondrial plasticity and synaptic plasticity crosstalk; in health and Alzheimer's disease. CNS Neurosci Ther 2024; 30:e14897. [PMID: 39097920 PMCID: PMC11298206 DOI: 10.1111/cns.14897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 06/19/2024] [Accepted: 07/18/2024] [Indexed: 08/06/2024] Open
Abstract
Synaptic plasticity is believed to underlie the cellular and molecular basis of memory formation. Mitochondria are one of the main organelles involved in metabolism and energy maintenance as plastic organelles that change morphologically and functionally in response to cellular needs and regulate synaptic function and plasticity through multiple mechanisms, including ATP generation, calcium homeostasis, and biogenesis. An increased neuronal activity enhances synaptic efficiency, during which mitochondria's spatial distribution and morphology change significantly. These organelles build up in the pre-and postsynaptic zones to produce ATP, which is necessary for several synaptic processes like neurotransmitter release and recycling. Mitochondria also regulate calcium homeostasis by buffering intracellular calcium, which ensures proper synaptic activity. Furthermore, mitochondria in the presynaptic terminal have distinct morphological properties compared to dendritic or postsynaptic mitochondria. This specialization enables precise control of synaptic activity and plasticity. Mitochondrial dysfunction has been linked to synaptic failure in many neurodegenerative disorders, like Alzheimer's disease (AD). In AD, malfunctioning mitochondria cause delays in synaptic vesicle release and recycling, ionic gradient imbalances, and mostly synaptic failure. This review emphasizes mitochondrial plasticity's contribution to synaptic function. It also explores the profound effect of mitochondrial malfunction on neurodegenerative disorders, focusing on AD, and provides an overview of how they sustain cellular health under normal conditions and how their malfunction contributes to neurodegenerative diseases, highlighting their potential as a therapeutic target for such conditions.
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Affiliation(s)
- Fatemeh Sayehmiri
- Neuroscience Research Center, Faculty of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Fereshteh Motamedi
- Neuroscience Research Center, Faculty of MedicineShahid Beheshti University of Medical SciencesTehranIran
- Faculty of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Zehra Batool
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological SciencesUniversity of KarachiKarachiPakistan
| | - Nima Naderi
- Department of Pharmacology and Toxicology, Faculty of PharmacyShahid Beheshti University of Medical SciencesTehranIran
| | | | - Anahita Zoghi
- Department of Neurology, Loghman Hakim HospitalShahid Beheshti University of Medical SciencesTehranIran
| | - Omidvar Rezaei
- Skull Base Research CenterLoghman Hakim Hospital, Shahid Beheshti University of Medical SciencesTehranIran
| | - Fariba Khodagholi
- Neuroscience Research Center, Faculty of MedicineShahid Beheshti University of Medical SciencesTehranIran
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13
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Pan K, Jinnah HA, Hess EJ, Smith Y, Villalba RM. Ultrastructural analysis of nigrostriatal dopaminergic terminals in a knockin mouse model of DYT1 dystonia. Eur J Neurosci 2024; 59:1407-1427. [PMID: 38123503 DOI: 10.1111/ejn.16197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 11/02/2023] [Accepted: 11/05/2023] [Indexed: 12/23/2023]
Abstract
DYT1 dystonia is associated with decreased striatal dopamine release. In this study, we examined the possibility that ultrastructural changes of nigrostriatal dopamine terminals could contribute to this neurochemical imbalance using a serial block face/scanning electron microscope (SBF/SEM) and three-dimensional reconstruction to analyse striatal tyrosine hydroxylase-immunoreactive (TH-IR) terminals and their synapses in a DYT1(ΔE) knockin (DYT1-KI) mouse model of DYT1 dystonia. Furthermore, to study possible changes in vesicle packaging capacity of dopamine, we used transmission electron microscopy to assess the synaptic vesicle size in striatal dopamine terminals. Quantitative comparative analysis of 80 fully reconstructed TH-IR terminals in the WT and DYT1-KI mice indicate (1) no significant difference in the volume of TH-IR terminals; (2) no major change in the proportion of axo-spinous versus axo-dendritic synapses; (3) no significant change in the post-synaptic density (PSD) area of axo-dendritic synapses, while the PSDs of axo-spinous synapses were significantly smaller in DYT1-KI mice; (4) no significant change in the contact area between TH-IR terminals and dendritic shafts or spines, while the ratio of PSD area/contact area decreased significantly for both axo-dendritic and axo-spinous synapses in DYT1-KI mice; (5) no significant difference in the mitochondria volume; and (6) no significant difference in the synaptic vesicle area between the two groups. Altogether, these findings suggest that abnormal morphometric changes of nigrostriatal dopamine terminals and their post-synaptic targets are unlikely to be a major source of reduced striatal dopamine release in DYT1 dystonia.
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Affiliation(s)
- Ke Pan
- Emory National Primate Research Center, Emory University, Atlanta, Georgia, USA
- Department of Physical Therapy & Human Movement Sciences, Northwestern University, Chicago, Illinois, USA
| | - Hyder A Jinnah
- Department of Neurology, Emory University, Atlanta, Georgia, USA
- Department of Human Genetics and Pediatrics, Emory University, Atlanta, Georgia, USA
| | - Ellen J Hess
- Department of Neurology, Emory University, Atlanta, Georgia, USA
- Department of Pharmacology and Chemical Biology, Emory University, Atlanta, Georgia, USA
| | - Yoland Smith
- Emory National Primate Research Center, Emory University, Atlanta, Georgia, USA
- Department of Neurology, Emory University, Atlanta, Georgia, USA
| | - Rosa M Villalba
- Emory National Primate Research Center, Emory University, Atlanta, Georgia, USA
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14
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Rathor L, Curry S, Park Y, McElroy T, Robles B, Sheng Y, Chen WW, Min K, Xiao R, Lee MH, Han SM. Mitochondrial stress in GABAergic neurons non-cell autonomously regulates organismal health and aging. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.20.585932. [PMID: 38585797 PMCID: PMC10996468 DOI: 10.1101/2024.03.20.585932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Mitochondrial stress within the nervous system can trigger non-cell autonomous responses in peripheral tissues. However, the specific neurons involved and their impact on organismal aging and health have remained incompletely understood. Here, we demonstrate that mitochondrial stress in γ-aminobutyric acid-producing (GABAergic) neurons in Caenorhabditis elegans ( C. elegans ) is sufficient to significantly alter organismal lifespan, stress tolerance, and reproductive capabilities. This mitochondrial stress also leads to significant changes in mitochondrial mass, energy production, and levels of reactive oxygen species (ROS). DAF-16/FoxO activity is enhanced by GABAergic neuronal mitochondrial stress and mediates the induction of these non-cell-autonomous effects. Moreover, our findings indicate that GABA signaling operates within the same pathway as mitochondrial stress in GABAergic neurons, resulting in non-cell-autonomous alterations in organismal stress tolerance and longevity. In summary, these data suggest the crucial role of GABAergic neurons in detecting mitochondrial stress and orchestrating non-cell-autonomous changes throughout the organism.
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15
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Miao Y, Xie L, Song J, Cai X, Yang J, Ma X, Chen S, Xie P. Unraveling the causes of sarcopenia: Roles of neuromuscular junction impairment and mitochondrial dysfunction. Physiol Rep 2024; 12:e15917. [PMID: 38225199 PMCID: PMC10789655 DOI: 10.14814/phy2.15917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 12/11/2023] [Accepted: 12/22/2023] [Indexed: 01/17/2024] Open
Abstract
Sarcopenia is a systemic skeletal muscle disease characterized by a decline in skeletal muscle mass and function. Originally defined as an age-associated condition, sarcopenia presently also encompasses muscular atrophy due to various pathological factors, such as intensive care unit-acquired weakness, inactivity, and malnutrition. The exact pathogenesis of sarcopenia is still unknown; herein, we review the pathological roles of the neuromuscular junction and mitochondria in this condition. Sarcopenia is caused by complex and interdependent pathophysiological mechanisms, including aging, neuromuscular junction impairment, mitochondrial dysfunction, insulin resistance, lipotoxicity, endocrine factors, oxidative stress, and inflammation. Among these, neuromuscular junction instability and mitochondrial dysfunction are particularly significant. Dysfunction in neuromuscular junction can lead to muscle weakness or paralysis. Mitochondria, which are plentiful in neurons and muscle fibers, play an important role in neuromuscular junction transmission. Therefore, impairments in both mitochondria and neuromuscular junction may be one of the key pathophysiological mechanisms leading to sarcopenia. Moreover, this article explores the structural and functional alterations in the neuromuscular junction and mitochondria in sarcopenia, suggesting that a deeper understanding of these changes could provide valuable insights for the prevention or treatment of sarcopenia.
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Affiliation(s)
- Yanmei Miao
- Department of Critical Care Medicine of the Third Affiliated Hospital (The First People's Hospital of Zunyi)Zunyi Medical UniversityZunyiChina
| | - Leiyu Xie
- Department of Critical Care Medicine of the Third Affiliated Hospital (The First People's Hospital of Zunyi)Zunyi Medical UniversityZunyiChina
| | - Jiamei Song
- Department of Nursing of Affiliated HospitalZunyi Medical UniversityZunyiChina
| | - Xing Cai
- Department of Critical Care Medicine of the Third Affiliated Hospital (The First People's Hospital of Zunyi)Zunyi Medical UniversityZunyiChina
| | - Jinghe Yang
- Department of Critical Care Medicine of the Third Affiliated Hospital (The First People's Hospital of Zunyi)Zunyi Medical UniversityZunyiChina
- Department of The First Clinical CollegeZunyi Medical UniversityZunyiChina
| | - Xinglong Ma
- Department of Critical Care Medicine of the Third Affiliated Hospital (The First People's Hospital of Zunyi)Zunyi Medical UniversityZunyiChina
| | - Shaolin Chen
- Department of Nursing of Affiliated HospitalZunyi Medical UniversityZunyiChina
| | - Peng Xie
- Department of Critical Care Medicine of the Third Affiliated Hospital (The First People's Hospital of Zunyi)Zunyi Medical UniversityZunyiChina
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16
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Verma H, Gangwar P, Yadav A, Yadav B, Rao R, Kaur S, Kumar P, Dhiman M, Taglialatela G, Mantha AK. Understanding the neuronal synapse and challenges associated with the mitochondrial dysfunction in mild cognitive impairment and Alzheimer's disease. Mitochondrion 2023; 73:19-29. [PMID: 37708950 DOI: 10.1016/j.mito.2023.09.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 07/26/2023] [Accepted: 09/12/2023] [Indexed: 09/16/2023]
Abstract
Synaptic mitochondria are crucial for maintaining synaptic activity due to their high energy requirements, substantial calcium (Ca2+) fluctuation, and neurotransmitter release at the synapse. To provide a continuous energy supply, neurons use special mechanisms to transport and distribute healthy mitochondria to the synapse while eliminating the damaged mitochondria from the synapse. Along the neuron, mitochondrial membrane potential (ψ) gradient exists and is highest in the somal region. Lower ψ in the synaptic region renders mitochondria more vulnerable to oxidative stress-mediated damage. Secondly, mitochondria become susceptible to the release of cytochrome c, and mitochondrial DNA (mtDNA) is not shielded from the reactive oxygen species (ROS) by the histone proteins (unlike nuclear DNA), leading to activation of caspases and pronounced oxidative DNA base damage, which ultimately causes synaptic loss. Both synaptic mitochondrial dysfunction and synaptic failure are crucial factors responsible for Alzheimer's disease (AD). Furthermore, amyloid beta (Aβ) and hyper-phosphorylated Tau, the two leading players of AD, exaggerate the disease-like pathological conditions by reducing the mitochondrial trafficking, blocking the bi-directional transport at the synapse, enhancing the mitochondrial fission via activating the mitochondrial fission proteins, enhancing the swelling of mitochondria by increasing the influx of water through mitochondrial permeability transition pore (mPTP) opening, as well as reduced ATP production by blocking the activity of complex I and complex IV. Mild cognitive impairment (MCI) is also associated with decline in cognitive ability caused by synaptic degradation. This review summarizes the challenges associated with the synaptic mitochondrial dysfunction linked to AD and MCI and the role of phytochemicals in restoring the synaptic activity and rendering neuroprotection in AD.
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Affiliation(s)
- Harkomal Verma
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Prabhakar Gangwar
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Anuradha Yadav
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Bharti Yadav
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Rashmi Rao
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Sharanjot Kaur
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Puneet Kumar
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Monisha Dhiman
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Giulio Taglialatela
- Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA
| | - Anil Kumar Mantha
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India.
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17
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Chou SM, Yen YH, Yuan F, Zhang SC, Chong CM. Neuronal Senescence in the Aged Brain. Aging Dis 2023; 14:1618-1632. [PMID: 37196117 PMCID: PMC10529744 DOI: 10.14336/ad.2023.0214] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 02/14/2023] [Indexed: 05/19/2023] Open
Abstract
Cellular senescence is a highly complicated cellular state that occurs throughout the lifespan of an organism. It has been well-defined in mitotic cells by various senescent features. Neurons are long-lived post-mitotic cells with special structures and functions. With age, neurons display morphological and functional changes, accompanying alterations in proteostasis, redox balance, and Ca2+ dynamics; however, it is ambiguous whether these neuronal changes belong to the features of neuronal senescence. In this review, we strive to identify and classify changes that are relatively specific to neurons in the aging brain and define them as features of neuronal senescence through comparisons with common senescent features. We also associate them with the functional decline of multiple cellular homeostasis systems, proposing the possibility that these systems are the main drivers of neuronal senescence. We hope this summary will serve as a steppingstone for further inputs on a comprehensive but relatively specific list of phenotypes for neuronal senescence and in particular their underlying molecular events during aging. This will in turn shine light on the association between neuronal senescence and neurodegeneration and lead to the development of strategies to perturb the processes.
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Affiliation(s)
- Shu-Min Chou
- Program in Neuroscience & Behavioral Disorders, Duke-NUS Medical School, 169857 Singapore, Singapore.
| | - Yu-Hsin Yen
- Program in Neuroscience & Behavioral Disorders, Duke-NUS Medical School, 169857 Singapore, Singapore.
| | - Fang Yuan
- Program in Neuroscience & Behavioral Disorders, Duke-NUS Medical School, 169857 Singapore, Singapore.
| | - Su-Chun Zhang
- Program in Neuroscience & Behavioral Disorders, Duke-NUS Medical School, 169857 Singapore, Singapore.
- Department of Neuroscience, Department of Neurology, Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA.
| | - Cheong-Meng Chong
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
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18
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Wang W, Zhao F, Lu Y, Siedlak SL, Fujioka H, Feng H, Perry G, Zhu X. Damaged mitochondria coincide with presynaptic vesicle loss and abnormalities in alzheimer's disease brain. Acta Neuropathol Commun 2023; 11:54. [PMID: 37004141 PMCID: PMC10067183 DOI: 10.1186/s40478-023-01552-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 03/16/2023] [Indexed: 04/03/2023] Open
Abstract
Loss of synapses is the most robust pathological correlate of Alzheimer's disease (AD)-associated cognitive deficits, although the underlying mechanism remains incompletely understood. Synaptic terminals have abundant mitochondria which play an indispensable role in synaptic function through ATP provision and calcium buffering. Mitochondrial dysfunction is an early and prominent feature in AD which could contribute to synaptic deficits. Here, using electron microscopy, we examined synapses with a focus on mitochondrial deficits in presynaptic axonal terminals and dendritic spines in cortical biopsy samples from clinically diagnosed AD and age-matched non-AD control patients. Synaptic vesicle density within the presynaptic axon terminals was significantly decreased in AD cases which appeared largely due to significantly decreased reserve pool, but there were significantly more presynaptic axons containing enlarged synaptic vesicles or dense core vesicles in AD. Importantly, there was reduced number of mitochondria along with significantly increased damaged mitochondria in the presynapse of AD which correlated with changes in SV density. Mitochondria in the post-synaptic dendritic spines were also enlarged and damaged in the AD biopsy samples. This study provided evidence of presynaptic vesicle loss as synaptic deficits in AD and suggested that mitochondrial dysfunction in both pre- and post-synaptic compartments contribute to synaptic deficits in AD.
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Affiliation(s)
- Wenzhang Wang
- Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH, 44106, USA
| | - Fanpeng Zhao
- Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH, 44106, USA
| | - Yubing Lu
- Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH, 44106, USA
| | - Sandra L Siedlak
- Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH, 44106, USA
| | - Hisashi Fujioka
- Cryo-EM Core Facility, Case Western Reserve University, Cleveland, OH, USA
| | - Hao Feng
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
| | - George Perry
- Department of Neuroscience, Developmental and Regenerative Biology, University of Texas, San Antonio, TX, USA
| | - Xiongwei Zhu
- Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH, 44106, USA.
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19
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Ahmad F, Ramamorthy S, Areeshi MY, Ashraf GM, Haque S. Isolated Mitochondrial Preparations and In organello Assays: A Powerful and Relevant Ex vivo Tool for Assessment of Brain (Patho)physiology. Curr Neuropharmacol 2023; 21:1433-1449. [PMID: 36872352 PMCID: PMC10324330 DOI: 10.2174/1570159x21666230303123555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 10/30/2022] [Accepted: 12/29/2022] [Indexed: 03/07/2023] Open
Abstract
Mitochondria regulate multiple aspects of neuronal development, physiology, plasticity, and pathology through their regulatory roles in bioenergetic, calcium, redox, and cell survival/death signalling. While several reviews have addressed these different aspects, a comprehensive discussion focussing on the relevance of isolated brain mitochondria and their utilities in neuroscience research has been lacking. This is relevant because the employment of isolated mitochondria rather than their in situ functional evaluation, offers definitive evidence of organelle-specificity, negating the interference from extra mitochondrial cellular factors/signals. This mini-review was designed primarily to explore the commonly employed in organello analytical assays for the assessment of mitochondrial physiology and its dysfunction, with a particular focus on neuroscience research. The authors briefly discuss the methodologies for biochemical isolation of mitochondria, their quality assessment, and cryopreservation. Further, the review attempts to accumulate the key biochemical protocols for in organello assessment of a multitude of mitochondrial functions critical for neurophysiology, including assays for bioenergetic activity, calcium and redox homeostasis, and mitochondrial protein translation. The purpose of this review is not to examine each and every method or study related to the functional assessment of isolated brain mitochondria, but rather to assemble the commonly used protocols of in organello mitochondrial research in a single publication. The hope is that this review will provide a suitable platform aiding neuroscientists to choose and apply the required protocols and tools to address their particular mechanistic, diagnostic, or therapeutic question dealing within the confines of the research area of mitochondrial patho-physiology in the neuronal perspective.
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Affiliation(s)
- Faraz Ahmad
- Department of Biotechnology, School of Bio Sciences and Technology (SBST), Vellore Institute of Technology, Vellore, 632014, India
| | - Siva Ramamorthy
- Department of Biotechnology, School of Bio Sciences and Technology (SBST), Vellore Institute of Technology, Vellore, 632014, India
| | - Mohammed Y. Areeshi
- Medical Laboratory Technology Department, College of Applied Medical Sciences, Jazan University, Jazan, 45142, Saudi Arabia
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, 45142, Saudi Arabia
| | - Ghulam Md. Ashraf
- Department of Medical Laboratory Sciences, College of Health Sciences, and Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, 45142, Saudi Arabia
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon
- Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
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20
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Liu D, Li J, Rong X, Li J, Peng Y, Shen Q. Cdk5 Promotes Mitochondrial Fission via Drp1 Phosphorylation at S616 in Chronic Ethanol Exposure-Induced Cognitive Impairment. Mol Neurobiol 2022; 59:7075-7094. [PMID: 36083519 DOI: 10.1007/s12035-022-03008-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 08/18/2022] [Indexed: 11/25/2022]
Abstract
Excessive alcohol consumption can lead to alterations in brain structure and function, even causing irreversible learning and memory disorders. The hippocampus is one of the most sensitive areas to alcohol neurotoxicity in the brain. Accumulating evidence indicates that mitochondrial dysfunction contributes to alcohol neurotoxicity. However, little is known about the underlying molecular mechanisms. In this study, we found that chronic exposure to ethanol caused abnormal mitochondrial fission/fusion and morphology by activating the mitochondrial fission protein dynamin-related protein 1 (Drp1) and upregulating Drp1 receptors, such as fission protein 1 (Fis1), mitochondrial dynamics protein of 49 kDa (Mid49), and mitochondrial fission factor (Mff), combined with decreasing optic atrophy 1 (Opa1) and mitochondrial fusion protein mitofusin 1 (Mfn1) levels. In addition, mitochondrial division inhibitor 1 (mdivi-1) abrogated ethanol-induced mitochondrial dysfunction and improved hippocampal synapses and cognitive function in ethanol-exposed mice. Chronic ethanol exposure also resulted in cyclin-dependent kinase 5 (Cdk5) overactivation, as shown by the increase in the levels of Cdk5 and its activator P25 in the hippocampus. Furthermore, a Cdk5/P25 inhibitor (roscovitine) or Cdk5 knockdown using small interfering RNA (LVi-Cdk5) exerted neuroprotection by inhibiting abnormal mitochondrial fission through Drp1 phosphorylation at Ser616 and mitochondrial translocation after chronic ethanol exposure. Taken together, the present study demonstrated that inhibition of aberrant Cdk5 activation attenuates hippocampal neuron injury and cognitive deficits induced by chronic exposure to ethanol through Drp1-mediated mitochondrial fission and mitochondrial dysfunction. Interfering with this pathway might serve as a potential therapeutic approach to prevent ethanol-induced neurotoxicity in the brain.
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Affiliation(s)
- Dandan Liu
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jiande Li
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaoming Rong
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jie Li
- The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ying Peng
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
| | - Qingyu Shen
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
- The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
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21
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Liu J, Qi J, Chen X, Li Z, Hong B, Ma H, Li G, Shen L, Liu D, Kong Y, Zhai H, Xie Q, Han H, Yang Y. Fear memory-associated synaptic and mitochondrial changes revealed by deep learning-based processing of electron microscopy data. Cell Rep 2022; 40:111151. [PMID: 35926462 DOI: 10.1016/j.celrep.2022.111151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 05/20/2022] [Accepted: 07/11/2022] [Indexed: 11/03/2022] Open
Abstract
Serial section electron microscopy (ssEM) can provide comprehensive 3D ultrastructural information of the brain with exceptional computational cost. Targeted reconstruction of subcellular structures from ssEM datasets is less computationally demanding but still highly informative. We thus developed a region-CNN-based deep learning method to identify, segment, and reconstruct synapses and mitochondria to explore the structural plasticity of synapses and mitochondria in the auditory cortex of mice subjected to fear conditioning. Upon reconstructing over 135,000 mitochondria and 160,000 synapses, we find that fear conditioning significantly increases the number of mitochondria but decreases their size and promotes formation of multi-contact synapses, comprising a single axonal bouton and multiple postsynaptic sites from different dendrites. Modeling indicates that such multi-contact configuration increases the information storage capacity of new synapses by over 50%. With high accuracy and speed in reconstruction, our method yields structural and functional insight into cellular plasticity associated with fear learning.
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Affiliation(s)
- Jing Liu
- National Laboratory of Pattern Recognition, Research Center for Brain-inspired Intelligence, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China; School of Artificial Intelligence, School of Future Technology, University of the Chinese Academy of Sciences, Beijing 101408, China
| | - Junqian Qi
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Xi Chen
- National Laboratory of Pattern Recognition, Research Center for Brain-inspired Intelligence, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China
| | - Zhenchen Li
- National Laboratory of Pattern Recognition, Research Center for Brain-inspired Intelligence, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China; School of Artificial Intelligence, School of Future Technology, University of the Chinese Academy of Sciences, Beijing 101408, China
| | - Bei Hong
- National Laboratory of Pattern Recognition, Research Center for Brain-inspired Intelligence, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China; School of Artificial Intelligence, School of Future Technology, University of the Chinese Academy of Sciences, Beijing 101408, China
| | - Hongtu Ma
- National Laboratory of Pattern Recognition, Research Center for Brain-inspired Intelligence, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China
| | - Guoqing Li
- National Laboratory of Pattern Recognition, Research Center for Brain-inspired Intelligence, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China
| | - Lijun Shen
- National Laboratory of Pattern Recognition, Research Center for Brain-inspired Intelligence, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China
| | - Danqian Liu
- Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yu Kong
- Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
| | - Hao Zhai
- National Laboratory of Pattern Recognition, Research Center for Brain-inspired Intelligence, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China; School of Artificial Intelligence, School of Future Technology, University of the Chinese Academy of Sciences, Beijing 101408, China
| | - Qiwei Xie
- Research Base of Beijing Modern Manufacturing Development, Beijing University of Technology, Beijing 100124, China.
| | - Hua Han
- National Laboratory of Pattern Recognition, Research Center for Brain-inspired Intelligence, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China; School of Artificial Intelligence, School of Future Technology, University of the Chinese Academy of Sciences, Beijing 101408, China; Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
| | - Yang Yang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
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22
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Zhou J, Li Q, Wu W, Zhang X, Zuo Z, Lu Y, Zhao H, Wang Z. Discovery of Novel Drug Candidates for Alzheimer’s Disease by Molecular Network Modeling. Front Aging Neurosci 2022; 14:850217. [PMID: 35493947 PMCID: PMC9051440 DOI: 10.3389/fnagi.2022.850217] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 02/25/2022] [Indexed: 11/16/2022] Open
Abstract
To identify the molecular mechanisms and novel therapeutic agents of late-onset Alzheimer’s disease (AD), we performed integrative network analysis using multiple transcriptomic profiles of human brains. With the hypothesis that AD pathology involves the whole cerebrum, we first identified co-expressed modules across multiple cerebral regions of the aging human brain. Among them, two modules (M3 and M8) consisting of 1,429 protein-coding genes were significantly enriched with AD-correlated genes. Differential expression analysis of microarray, bulk RNA-sequencing (RNA-seq) data revealed the dysregulation of M3 and M8 across different cerebral regions in both normal aging and AD. The cell-type enrichment analysis and differential expression analysis at the single-cell resolution indicated the extensive neuronal vulnerability in AD pathogenesis. Transcriptomic-based drug screening from Connectivity Map proposed Gly-His-Lys acetate salt (GHK) as a potential drug candidate that could probably restore the dysregulated genes of the M3 and M8 network. Pretreatment with GHK showed a neuroprotective effect against amyloid-beta-induced injury in differentiated human neuron-like SH-SY5Y cells. Taken together, our findings uncover a dysregulated network disrupted across multiple cerebral regions in AD and propose pretreatment with GHK as a novel neuroprotective strategy against AD.
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Affiliation(s)
- Jiaxin Zhou
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qingyong Li
- Medical Research Center, Sun Yat-sen Memorial Hospital, Guangzhou, China
| | - Wensi Wu
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaojun Zhang
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhiyi Zuo
- Department of Anesthesiology, University of Virginia, Charlottesville, VA, United States
| | - Yanan Lu
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Huiying Zhao
- Medical Research Center, Sun Yat-sen Memorial Hospital, Guangzhou, China
- *Correspondence: Huiying Zhao,
| | - Zhi Wang
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Zhi Wang,
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23
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Panes JD, Wendt A, Ramirez-Molina O, Castro PA, Fuentealba J. Deciphering the role of PGC-1α in neurological disorders: from mitochondrial dysfunction to synaptic failure. Neural Regen Res 2022; 17:237-245. [PMID: 34269182 PMCID: PMC8463972 DOI: 10.4103/1673-5374.317957] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
The onset and mechanisms underlying neurodegenerative diseases remain uncertain. The main features of neurodegenerative diseases have been related with cellular and molecular events like neuronal loss, mitochondrial dysfunction and aberrant accumulation of misfolded proteins or peptides in specific areas of the brain. The most prevalent neurodegenerative diseases belonging to age-related pathologies are Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis. Interestingly, mitochondrial dysfunction has been observed to occur during the early onset of several neuropathological events associated to neurodegenerative diseases. The master regulator of mitochondrial quality control and energetic metabolism is the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Additionally, it has been observed that PGC-1α appears to be a key factor in maintaining neuronal survival and synaptic transmission. In fact, PGC-1α downregulation in different brain areas (hippocampus, substantia nigra, cortex, striatum and spinal cord) that occurs in function of neurological damage including oxidative stress, neuronal loss, and motor disorders has been seen in several animal and cellular models of neurodegenerative diseases. Current evidence indicates that PGC-1α upregulation may serve as a potent therapeutic approach against development and progression of neuronal damage. Remarkably, increasing evidence shows that PGC-1α deficient mice have neurodegenerative diseases-like features, as well as neurological abnormalities. Finally, we discuss recent studies showing novel specific PGC-1α isoforms in the central nervous system that appear to exert a key role in the age of onset of neurodegenerative diseases and have a neuroprotective function in the central nervous system, thus opening a new molecular strategy for treatment of neurodegenerative diseases. The purpose of this review is to provide an up-to-date overview of the PGC-1α role in the physiopathology of neurodegenerative diseases, as well as establish the importance of PGC-1α function in synaptic transmission and neuronal survival.
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Affiliation(s)
- Jessica D Panes
- Laboratorio de Screening de Compuestos Neuroactivos (LSCN), Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Aline Wendt
- Laboratorio de Screening de Compuestos Neuroactivos (LSCN), Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Oscar Ramirez-Molina
- Laboratorio de Screening de Compuestos Neuroactivos (LSCN), Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Patricio A Castro
- Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Jorge Fuentealba
- Laboratorio de Screening de Compuestos Neuroactivos (LSCN), Departamento de Fisiología; Centro de Investigaciones Avanzadas en Biomedicina (CIAB-UdeC), Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
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24
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Sarkar A, Hameed R, Mishra A, Bhatta RS, Nazir A. Genetic modulators associated with regulatory surveillance of mitochondrial quality control, play a key role in regulating stress pathways and longevity in C. elegans. Life Sci 2021; 290:120226. [PMID: 34953889 DOI: 10.1016/j.lfs.2021.120226] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/22/2021] [Accepted: 12/08/2021] [Indexed: 12/21/2022]
Abstract
The multi-factorial Parkinson's disease (PD) is known to be associated with mitochondrial dysfunction, endoplasmic reticulum stress, alpha synuclein aggregation and dopaminergic neuronal death, with oxidative stress being a common denominator to these underlying processes. The perception of mitochondria being 'just ATP producing compartments' have been counterpoised as studies, particularly related to PD, have underlined their strong role in cause and progression of the disease. During PD pathogenesis, neurons encounter chronic stress conditions mainly due to failure of Mitochondrial Quality Control (MQC) machinery. To dissect the regulatory understanding of mitochondrial dysfunction during neurological disease progression, we endeavored to identify key regulatory endpoints that control multiple facets of MQC machinery. Our studies, employing transgenic C. elegans strain expressing human α-synuclein, led us to identification of mitochondrial genes nuo-5 (involved in oxidative phosphorylation), F25B4.7 (exhibits ATP transmembrane transporter activity) and C05D11.9 (having ribonuclease activity), which form predicted downstream targets of most elevated and down-regulated mi-RNA molecules. RNAi mediated silencing, gene ontology and functional genomics analysis studies demonstrated their role in modulating major MQC pathways. The attenuated MQC pathways mainly affected clearance of misfolded and aggregated proteins, redox homeostasis and longevity with compromised dopaminergic functions. Overexpression of the mitochondrial genes by 3 beta-hydroxyl steroid, Tomatidine, was found to curtail the redox imbalance thus leading to amelioration of effects associated with PD and an increase in the lifespan of treated nematodes. Therefore, this study unveils the regulatory role of mitochondrial genes as critical modulators of stress control involved in effects associated with PD pathogenesis.
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Affiliation(s)
- Arunabh Sarkar
- Division of Neuroscience and Aging Biology, CSIR-Central Drug Research Institute, Lucknow, UP, India; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP, India
| | - Rohil Hameed
- Division of Neuroscience and Aging Biology, CSIR-Central Drug Research Institute, Lucknow, UP, India; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP, India
| | - Anjali Mishra
- Division of Neuroscience and Aging Biology, CSIR-Central Drug Research Institute, Lucknow, UP, India; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP, India
| | - Rabi Sankar Bhatta
- Division of Neuroscience and Aging Biology, CSIR-Central Drug Research Institute, Lucknow, UP, India; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP, India
| | - Aamir Nazir
- Division of Neuroscience and Aging Biology, CSIR-Central Drug Research Institute, Lucknow, UP, India; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP, India.
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25
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Chen C, Yang C, Wang J, Huang X, Yu H, Li S, Li S, Zhang Z, Liu J, Yang X, Liu GP. Melatonin ameliorates cognitive deficits through improving mitophagy in a mouse model of Alzheimer's disease. J Pineal Res 2021; 71:e12774. [PMID: 34617321 DOI: 10.1111/jpi.12774] [Citation(s) in RCA: 107] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 08/23/2021] [Accepted: 10/04/2021] [Indexed: 12/11/2022]
Abstract
While melatonin is known to have protective effects in mitochondria-related diseases, aging, and neurodegenerative disorders, there is poor understanding of the effects of melatonin treatment on mitophagy in Alzheimer's disease (AD). We used proteomic analysis to investigate the effects and underlying molecular mechanisms of oral melatonin treatment on mitophagy in the hippocampus of 4-month-old wild-type mice versus age-matched 5 × FAD mice, an animal model of AD. 5 × FAD mice showed disordered mitophagy and mitochondrial dysfunction as revealed by increased mtDNA, mitochondrial marker proteins and MDA production, decreased electron transport chain proteins and ATP levels, and co-localization of Lamp1 and Tomm20. Melatonin treatment reversed the abnormal expression of proteins in the signaling pathway of lysosomes, pathologic phagocytosis of microglia, and mitochondrial energy metabolism. Moreover, melatonin restored mitophagy by improving mitophagosome-lysosome fusion via Mcoln1, and thus, ameliorated mitochondrial functions, attenuated Aβ pathology, and improved cognition. Concurrent treatment with chloroquine and melatonin blocked the positive behavioral and biochemical effects of administration with melatonin alone. Taken in concert, these results suggest that melatonin reduces AD-related deficits in mitophagy such that the drug should be considered as a therapeutic candidate for the treatment of AD.
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Affiliation(s)
- Chongyang Chen
- Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chao Yang
- Cognitive Impairment Ward of Neurology Department, the Third Affiliated Hospital of Shenzhen University Medical College, Shenzhen, Guangdong, China
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jing Wang
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Xi Huang
- Department of Neurology, Shenzhen People's Hospital (First Affiliated Hospital of Southern University of Science and Technology), Second Clinical College, Jinan University, Shenzhen, Guangdong Province, China
| | - Haitao Yu
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Shangming Li
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Shupeng Li
- School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Zaijun Zhang
- Institute of New Drug Research and Guangzhou, Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China
| | - Jianjun Liu
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Xifei Yang
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Gong-Ping Liu
- Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Co-innovation Center of Neurodegeneration, Nantong University, Nantong, JS, China
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26
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Spadini S, Racchetti G, Adiletta A, Lamanna J, Moro AS, Ferro M, Zimarino V, Malgaroli A. A novel integrated approach to estimate the mitochondrial content of neuronal cells and brain tissues. J Neurosci Methods 2021; 363:109351. [PMID: 34481832 DOI: 10.1016/j.jneumeth.2021.109351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 07/28/2021] [Accepted: 08/31/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Mitochondria and their dynamics fuel most cellular processes both in physiological and pathological conditions. In the central nervous system, mitochondria sustain synaptic transmission and plasticity via multiple mechanisms which include their redistribution and/or expansion to higher energy demanding sites, sustaining activity changes and promoting morphological circuit adaptations. NEW METHOD To be able to evaluate changes in mitochondrial number and protein phenotype, we propose a novel methodological approach where the simultaneous analysis of both mitochondrial DNA and protein content is performed on each individual microsample, avoiding non-homogeneous loss of material. RESULTS We validated this method on neuronal-like cells and tissue samples and obtained estimates for the mitochondrial/genomic DNA ratio as well as for the abundance of protein counterparts. When the mitochondrial content per cell was evaluated in different brain areas, our results matched the known regional variation in aerobic-anaerobic metabolism. When long-term potentiation (LTP) was induced on hippocampal neurons, we detected increases in the abundance of mitochondria that correlated with the degree of synaptic enhancement. CONCLUSIONS Our approach can be effectively used to study the mitochondrial content andits changes in different brain cells and tissues.
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Affiliation(s)
- Sara Spadini
- Center for Behavioral Neuroscience and Communication (BNC), Vita-Salute San Raffaele University, Via Olgettina 58, Milan 20132, Italy; Faculty of Psychology, Vita-Salute San Raffaele University, Milan, Italy
| | - Gabriella Racchetti
- Division of Neuroscience, Scientific Institute Ospedale San Raffaele, Milan, Italy
| | - Alice Adiletta
- Center for Behavioral Neuroscience and Communication (BNC), Vita-Salute San Raffaele University, Via Olgettina 58, Milan 20132, Italy; Center for Mind/Brain Sciences (CIMeC), University of Trento, Rovereto, Italy
| | - Jacopo Lamanna
- Center for Behavioral Neuroscience and Communication (BNC), Vita-Salute San Raffaele University, Via Olgettina 58, Milan 20132, Italy; Faculty of Psychology, Vita-Salute San Raffaele University, Milan, Italy
| | - Andrea Stefano Moro
- Center for Behavioral Neuroscience and Communication (BNC), Vita-Salute San Raffaele University, Via Olgettina 58, Milan 20132, Italy; Department of Psychology, Sigmund Freud University, Milan, Italy
| | - Mattia Ferro
- Center for Behavioral Neuroscience and Communication (BNC), Vita-Salute San Raffaele University, Via Olgettina 58, Milan 20132, Italy; Department of Psychology, Sigmund Freud University, Milan, Italy
| | - Vincenzo Zimarino
- Division of Neuroscience, Scientific Institute Ospedale San Raffaele, Milan, Italy
| | - Antonio Malgaroli
- Center for Behavioral Neuroscience and Communication (BNC), Vita-Salute San Raffaele University, Via Olgettina 58, Milan 20132, Italy; Faculty of Psychology, Vita-Salute San Raffaele University, Milan, Italy.
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27
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Guo W, Tang ZY, Cai ZY, Zhao WE, Yang J, Wang XP, Ji J, Huang XX, Sun XL. Iptakalim alleviates synaptic damages via targeting mitochondrial ATP-sensitive potassium channel in depression. FASEB J 2021; 35:e21581. [PMID: 33871072 DOI: 10.1096/fj.202100124rr] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 03/18/2021] [Accepted: 03/25/2021] [Indexed: 12/28/2022]
Abstract
Synaptic plasticity damages play a crucial role in the onset and development of depression, especially in the hippocampus, which is more susceptible to stress and the most frequently studied brain region in depression. And, mitochondria have a major function in executing the complex processes of neurotransmission and plasticity. We have previously demonstrated that Iptakalim (Ipt), a new ATP-sensitive potassium (K-ATP) channel opener, could improve the depressive-like behavior in mice. But the underlying mechanisms are not well understood. The present study demonstrated that Ipt reversed depressive-like phenotype in vivo (chronic mild stress-induced mice model of depression) and in vitro (corticosterone-induced cellular model). Further study showed that Ipt could upregulate the synaptic-related proteins postsynaptic density 95 (PSD 95) and synaptophysin (SYN), and alleviated the synaptic structure damage. Moreover, Ipt could reverse the abnormal mitochondrial fission and fusion, as well as the reduced mitochondrial ATP production and collapse of mitochondrial membrane potential in depressive models. Knocking down the mitochondrial ATP-sensitive potassium (Mito-KATP) channel subunit MitoK partly blocked the above effects of Ipt. Therefore, our results reveal that Ipt can alleviate the abnormal mitochondrial dynamics and function depending on MitoK, contributing to improve synaptic plasticity and exert antidepressive effects. These findings provide a candidate compound and a novel target for antidepressive therapy.
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Affiliation(s)
- Wei Guo
- Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Zi-Yang Tang
- Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Zhen-Yu Cai
- Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Wen-E Zhao
- Analysis Center, Nanjing Medical University, Nanjing, China
| | - Jin Yang
- Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Xi-Peng Wang
- Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Juan Ji
- Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Xin-Xin Huang
- Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Xiu-Lan Sun
- Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Center for Global Health, Nanjing Medical University, Nanjing, China.,The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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28
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Changes in synaptic proteins of the complex PSD-95/NMDA receptor/nNOS and mitochondrial dysfunction after levocabastine treatment. Neurochem Int 2021; 148:105100. [PMID: 34139299 DOI: 10.1016/j.neuint.2021.105100] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 05/26/2021] [Accepted: 06/10/2021] [Indexed: 11/22/2022]
Abstract
Nitric oxide generation is related to the activity of certain proteins located at synaptic sites. Previous findings show that NOS activity, nNOS protein expression, respiratory parameters and mitochondrial complex activities are altered in rat cerebral cortex by administration of levocabastine, an antagonist of histamine H1 and neurotensin NTS2 receptors. ATP provision by mitochondria may play an important role in the functional interaction between synaptic proteins NMDA receptor and PSD-95 with NO synthesis. In this context, our purpose was to evaluate the effect of levocabastine administration on protein expression of PSD-95, GluN2B and iNOS, as well as on mitochondrial ATP production. Male Wistar rats received a single (i.p.) dose of levocabastine (50 μg/kg) or saline solution (controls) and were decapitated 18 h later. Mitochondrial and synaptosomal membrane fractions were isolated from cerebral cortex by differential and sucrose gradient centrifugation. Expression of synaptic proteins was evaluated by Western blot assays in synaptosomal membrane fractions. Oxygen consumption, mitochondrial membrane potential and ATP production rate were determined in fresh crude mitochondrial fractions. After levocabastine treatment, protein expression of PSD-95, GluN2B and β-actin decreased 97, 45 and 55%, respectively, whereas that of iNOS enhanced 3.5-fold versus controls. In crude mitochondrial fractions levocabastine administration reduced roughly 15% respiratory control rate as assayed with malate-glutamate or succinate as substrates, decreased mitochondrial membrane potential (21%), and ATP production rates (57%). Results suggested that levocabastine administration induces alterations in synaptic proteins of the protein complex PSD-95/NMDA receptor/nNOS and in neuron cytoskeleton. Mitochondrial bioenergetics impairment may play a role in the functional link between synaptic proteins and NO synthesis.
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29
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Fu X, An Y, Wang H, Li P, Lin J, Yuan J, Yue R, Jin Y, Gao J, Chai R. Deficiency of Klc2 Induces Low-Frequency Sensorineural Hearing Loss in C57BL/6 J Mice and Human. Mol Neurobiol 2021; 58:4376-4391. [PMID: 34014435 DOI: 10.1007/s12035-021-02422-w] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 05/05/2021] [Indexed: 12/19/2022]
Abstract
The transport system in cochlear hair cells (HCs) is important for their function, and the kinesin family of proteins transports numerous cellular cargos via the microtubule network in the cytoplasm. Here, we found that Klc2 (kinesin light chain 2), the light chain of kinesin-1 that mediates cargo binding and regulates kinesin-1 motility, is essential for cochlear function. We generated mice lacking Klc2, and they suffered from low-frequency hearing loss as early as 1 month of age. We demonstrated that deficiency of Klc2 resulted in abnormal transport of mitochondria and the down-regulation of the GABAA receptor family. In addition, whole-genome sequencing (WGS) of patient showed that KLC2 was related to low-frequency hearing in human. Hence, to explore therapeutic approaches, we developed adeno-associated virus containing the Klc2 wide-type cDNA sequence, and Klc2-null mice delivered virus showed apparent recovery, including decreased ABR threshold and reduced out hair cell (OHC) loss. In summary, we show that the kinesin transport system plays an indispensable and special role in cochlear HC function in mice and human and that mitochondrial localization is essential for HC survival.
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Affiliation(s)
- Xiaolong Fu
- State Key Laboratory of Bioelectronics, School of Life Sciences and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China.,College of Laboratory Animal & Shandong Laboratory Animal Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Yachun An
- School of Life Science, Shandong University, Qingdao, China
| | - Hongyang Wang
- College of Otolaryngology, Head and Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China
| | - Peipei Li
- School of Life Science, Shandong University, Qingdao, China
| | - Jing Lin
- Waksman Institute, the State University of New Jersey, RutgersNew Brunswick, NJ, USA
| | - Jia Yuan
- State Key Laboratory of Bioelectronics, School of Life Sciences and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China
| | - Rongyu Yue
- Department of Otolaryngology-Head and Neck Surgery, Provincial Hospital Affiliated To Shandong University, Jinan, China
| | - Yecheng Jin
- School of Life Science, Shandong University, Qingdao, China
| | - Jiangang Gao
- College of Laboratory Animal & Shandong Laboratory Animal Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
| | - Renjie Chai
- State Key Laboratory of Bioelectronics, School of Life Sciences and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China. .,College of Laboratory Animal & Shandong Laboratory Animal Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China. .,Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Science, Beijing, China.
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30
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Callens M, Kraskovskaya N, Derevtsova K, Annaert W, Bultynck G, Bezprozvanny I, Vervliet T. The role of Bcl-2 proteins in modulating neuronal Ca 2+ signaling in health and in Alzheimer's disease. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2021; 1868:118997. [PMID: 33711363 PMCID: PMC8041352 DOI: 10.1016/j.bbamcr.2021.118997] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 02/23/2021] [Accepted: 02/25/2021] [Indexed: 12/11/2022]
Abstract
The family of B-cell lymphoma-2 (Bcl-2) proteins exerts key functions in cellular health. Bcl-2 primarily acts in mitochondria where it controls the initiation of apoptosis. However, during the last decades, it has become clear that this family of proteins is also involved in controlling intracellular Ca2+ signaling, a critical process for the function of most cell types, including neurons. Several anti- and pro-apoptotic Bcl-2 family members are expressed in neurons and impact neuronal function. Importantly, expression levels of neuronal Bcl-2 proteins are affected by age. In this review, we focus on the emerging roles of Bcl-2 proteins in neuronal cells. Specifically, we discuss how their dysregulation contributes to the onset, development, and progression of neurodegeneration in the context of Alzheimer's disease (AD). Aberrant Ca2+ signaling plays an important role in the pathogenesis of AD, and we propose that dysregulation of the Bcl-2-Ca2+ signaling axis may contribute to the progression of AD and that herein, Bcl-2 may constitute a potential therapeutic target for the treatment of AD.
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Affiliation(s)
- Manon Callens
- KU Leuven, Laboratory of Molecular & Cellular Signaling, Department of Cellular & Molecular Medicine, Campus Gasthuisberg O/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium
| | - Nina Kraskovskaya
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg State Polytechnic University, Saint Petersburg, Russia
| | - Kristina Derevtsova
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg State Polytechnic University, Saint Petersburg, Russia
| | - Wim Annaert
- Laboratory for Membrane Trafficking, VIB Center for Brain and Disease Research & KU Leuven, Department of Neurosciences, Gasthuisberg, O&N5, Rm 7.357, B-3000 Leuven, Belgium
| | - Geert Bultynck
- KU Leuven, Laboratory of Molecular & Cellular Signaling, Department of Cellular & Molecular Medicine, Campus Gasthuisberg O/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium.
| | - Ilya Bezprozvanny
- Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg State Polytechnic University, Saint Petersburg, Russia; Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX, United States.
| | - Tim Vervliet
- KU Leuven, Laboratory of Molecular & Cellular Signaling, Department of Cellular & Molecular Medicine, Campus Gasthuisberg O/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium
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31
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Datta S, Jaiswal M. Mitochondrial calcium at the synapse. Mitochondrion 2021; 59:135-153. [PMID: 33895346 DOI: 10.1016/j.mito.2021.04.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 03/28/2021] [Accepted: 04/13/2021] [Indexed: 12/15/2022]
Abstract
Mitochondria are dynamic organelles, which serve various purposes, including but not limited to the production of ATP and various metabolites, buffering ions, acting as a signaling hub, etc. In recent years, mitochondria are being seen as the central regulators of cellular growth, development, and death. Since neurons are highly specialized cells with a heavy metabolic demand, it is not surprising that neurons are one of the most mitochondria-rich cells in an animal. At synapses, mitochondrial function and dynamics is tightly regulated by synaptic calcium. Calcium influx during synaptic activity causes increased mitochondrial calcium influx leading to an increased ATP production as well as buffering of synaptic calcium. While increased ATP production is required during synaptic transmission, calcium buffering by mitochondria is crucial to prevent faulty neurotransmission and excitotoxicity. Interestingly, mitochondrial calcium also regulates the mobility of mitochondria within synapses causing mitochondria to halt at the synapse during synaptic transmission. In this review, we summarize the various roles of mitochondrial calcium at the synapse.
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Affiliation(s)
- Sayantan Datta
- Tata Institute of Fundamental Research, Hyderabad, India
| | - Manish Jaiswal
- Tata Institute of Fundamental Research, Hyderabad, India.
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32
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Jia Q, Sieburth D. Mitochondrial hydrogen peroxide positively regulates neuropeptide secretion during diet-induced activation of the oxidative stress response. Nat Commun 2021; 12:2304. [PMID: 33863916 PMCID: PMC8052458 DOI: 10.1038/s41467-021-22561-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 03/17/2021] [Indexed: 12/17/2022] Open
Abstract
Mitochondria play a pivotal role in the generation of signals coupling metabolism with neurotransmitter release, but a role for mitochondrial-produced ROS in regulating neurosecretion has not been described. Here we show that endogenously produced hydrogen peroxide originating from axonal mitochondria (mtH2O2) functions as a signaling cue to selectively regulate the secretion of a FMRFamide-related neuropeptide (FLP-1) from a pair of interneurons (AIY) in C. elegans. We show that pharmacological or genetic manipulations that increase mtH2O2 levels lead to increased FLP-1 secretion that is dependent upon ROS dismutation, mitochondrial calcium influx, and cysteine sulfenylation of the calcium-independent PKC family member PKC-1. mtH2O2-induced FLP-1 secretion activates the oxidative stress response transcription factor SKN-1/Nrf2 in distal tissues and protects animals from ROS-mediated toxicity. mtH2O2 levels in AIY neurons, FLP-1 secretion and SKN-1 activity are rapidly and reversibly regulated by exposing animals to different bacterial food sources. These results reveal a previously unreported role for mtH2O2 in linking diet-induced changes in mitochondrial homeostasis with neuropeptide secretion.
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Affiliation(s)
- Qi Jia
- PIBBS program, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Derek Sieburth
- Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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33
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Viegas FO, Neuhauss SCF. A Metabolic Landscape for Maintaining Retina Integrity and Function. Front Mol Neurosci 2021; 14:656000. [PMID: 33935647 PMCID: PMC8081888 DOI: 10.3389/fnmol.2021.656000] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/22/2021] [Indexed: 01/27/2023] Open
Abstract
Neurons have high metabolic demands that are almost exclusively met by glucose supplied from the bloodstream. Glucose is utilized in complex metabolic interactions between neurons and glia cells, described by the astrocyte-neuron lactate shuttle (ANLS) hypothesis. The neural retina faces similar energy demands to the rest of the brain, with additional high anabolic needs to support continuous renewal of photoreceptor outer segments. This demand is met by a fascinating variation of the ANLS in which photoreceptors are the central part of a metabolic landscape, using glucose and supplying surrounding cells with metabolic intermediates. In this review we summarize recent evidence on how neurons, in particular photoreceptors, meet their energy and biosynthetic requirements by comprising a metabolic landscape of interdependent cells.
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Affiliation(s)
- Filipe O Viegas
- Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.,Life Science Zurich Graduate School, Ph.D. Program in Molecular Life Sciences, Zurich, Switzerland
| | - Stephan C F Neuhauss
- Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
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34
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Microglial Pruning: Relevance for Synaptic Dysfunction in Multiple Sclerosis and Related Experimental Models. Cells 2021; 10:cells10030686. [PMID: 33804596 PMCID: PMC8003660 DOI: 10.3390/cells10030686] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/12/2021] [Accepted: 03/17/2021] [Indexed: 12/11/2022] Open
Abstract
Microglia, besides being able to react rapidly to a wide range of environmental changes, are also involved in shaping neuronal wiring. Indeed, they actively participate in the modulation of neuronal function by regulating the elimination (or “pruning”) of weaker synapses in both physiologic and pathologic processes. Mounting evidence supports their crucial role in early synaptic loss, which is emerging as a hallmark of several neurodegenerative diseases, including multiple sclerosis (MS) and its preclinical models. MS is an inflammatory, immune-mediated pathology of the white matter in which demyelinating lesions may cause secondary neuronal death. Nevertheless, primitive grey matter (GM) damage is emerging as an important contributor to patients’ long-term disability, since it has been associated with early and progressive cognitive decline (CD), which seriously worsens the quality of life of MS patients. Widespread synapse loss even in the absence of demyelination, axon degeneration and neuronal death has been demonstrated in different GM structures, thus raising the possibility that synaptic dysfunction could be an early and possibly independent event in the neurodegenerative process associated with MS. This review provides an overview of microglial-dependent synapse elimination in the neuroinflammatory process that underlies MS and its experimental models.
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35
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Scaini G, Andrews T, Lima CNC, Benevenuto D, Streck EL, Quevedo J. Mitochondrial dysfunction as a critical event in the pathophysiology of bipolar disorder. Mitochondrion 2021; 57:23-36. [PMID: 33340709 PMCID: PMC10494232 DOI: 10.1016/j.mito.2020.12.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/18/2020] [Accepted: 12/10/2020] [Indexed: 01/02/2023]
Abstract
The understanding of the pathophysiology of bipolar disorder (BD) remains modest, despite recent advances in neurobiological research. The mitochondrial dysfunction hypothesis of bipolar disorder has been corroborated by several studies involving postmortem brain analysis, neuroimaging, and specific biomarkers in both rodent models and humans. Evidence suggests that BD might be related to abnormal mitochondrial morphology and dynamics, neuroimmune dysfunction, and atypical mitochondrial metabolism and oxidative stress pathways. Mitochondrial dysfunction in mood disorders is also associated with abnormal Ca2+ levels, glutamate excitotoxicity, an imbalance between pro- and antiapoptotic proteins towards apoptosis, abnormal gene expression of electron transport chain complexes, and decreased ATP synthesis. This paper aims to review and discuss the implications of mitochondrial dysfunction in BD etiology and to explore mitochondria as a potential target for novel therapeutic agents.
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Affiliation(s)
- Giselli Scaini
- Translational Psychiatry Program, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences at McGovern Medical School, The University of Texas Health Science Center at Houston (UT Health), Houston, TX, USA
| | - Taylor Andrews
- Translational Psychiatry Program, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences at McGovern Medical School, The University of Texas Health Science Center at Houston (UT Health), Houston, TX, USA
| | - Camila N C Lima
- Translational Psychiatry Program, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences at McGovern Medical School, The University of Texas Health Science Center at Houston (UT Health), Houston, TX, USA
| | - Deborah Benevenuto
- Translational Psychiatry Program, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences at McGovern Medical School, The University of Texas Health Science Center at Houston (UT Health), Houston, TX, USA
| | - Emilio L Streck
- Laboratory of Experimental Neurology, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - João Quevedo
- Translational Psychiatry Program, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences at McGovern Medical School, The University of Texas Health Science Center at Houston (UT Health), Houston, TX, USA; Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil; Center of Excellence on Mood Disorders, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences at McGovern Medical School, The University of Texas Health Science Center at Houston (UT Health), Houston, TX, USA; Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX, USA.
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36
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An iPSC-based neural model of sialidosis uncovers glycolytic impairment-causing presynaptic dysfunction and deregulation of Ca 2+ dynamics. Neurobiol Dis 2021; 152:105279. [PMID: 33516873 DOI: 10.1016/j.nbd.2021.105279] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/21/2022] Open
Abstract
Sialidosis is a neuropathic lysosomal storage disease caused by a deficiency in the NEU1 gene-encoding lysosomal neuraminidase and characterized by abnormal accumulation of undigested sialyl-oligoconjugates in systemic organs including brain. Although patients exhibit neurological symptoms, the underlying neuropathological mechanism remains unclear. Here, we generated induced pluripotent stem cells (iPSCs) from skin fibroblasts with sialidosis and induced the differentiation into neural progenitor cells (NPCs) and neurons. Sialidosis NPCs and neurons mimicked the disease-like phenotypes including reduced neuraminidase activity, accumulation of sialyl-oligoconjugates and lysosomal expansions. Functional analysis also revealed that sialidosis neurons displayed two distinct abnormalities, defective exocytotic glutamate release and augmented α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR)-mediated Ca2+ influx. These abnormalities were restored by overexpression of the wild-type NEU1 gene, demonstrating causative role of neuraminidase deficiency in functional impairments of disease neurons. Comprehensive proteomics analysis revealed the significant reduction of SNARE proteins and glycolytic enzymes in synaptosomal fraction, with downregulation of ATP production. Bypassing the glycolysis by treatment of pyruvate, which is final metabolite of glycolysis pathway, improved both the synaptsomal ATP production and the exocytotic function. We also found that upregulation of AMPAR and L-type voltage dependent Ca2+ channel (VDCC) subunits in disease neurons, with the restoration of AMPAR-mediated Ca2+ over-load by treatment of antagonists for the AMPAR and L-type VDCC. Our present study provides new insights into both the neuronal pathophysiology and potential therapeutic strategy for sialidosis.
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37
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de Jongh R, Spijkers XM, Pasteuning-Vuhman S, Vulto P, Pasterkamp RJ. Neuromuscular junction-on-a-chip: ALS disease modeling and read-out development in microfluidic devices. J Neurochem 2021; 157:393-412. [PMID: 33382092 DOI: 10.1111/jnc.15289] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 12/24/2020] [Accepted: 12/28/2020] [Indexed: 12/21/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disease affecting upper and lower motor neurons with no cure available. Clinical and animal studies reveal that the neuromuscular junction (NMJ), a synaptic connection between motor neurons and skeletal muscle fibers, is highly vulnerable in ALS and suggest that NMJ defects may occur at the early stages of the disease. However, mechanistic insight into how NMJ dysfunction relates to the onset and progression of ALS is incomplete, which hampers therapy development. This is, in part, caused by a lack of robust in vitro models. The ability to combine microfluidic and induced pluripotent stem cell (iPSC) technologies has opened up new avenues for studying molecular and cellular ALS phenotypes in vitro. Microfluidic devices offer several advantages over traditional culture approaches when modeling the NMJ, such as the spatial separation of different cell types and increased control over the cellular microenvironment. Moreover, they are compatible with 3D cell culture, which enhances NMJ functionality and maturity. Here, we review how microfluidic technology is currently being employed to develop more reliable in vitro NMJ models. To validate and phenotype such models, various morphological and functional read-outs have been developed. We describe and discuss the relevance of these read-outs and specifically illustrate how these read-outs have enhanced our understanding of NMJ pathology in ALS. Finally, we share our view on potential future directions and challenges.
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Affiliation(s)
- Rianne de Jongh
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
| | - Xandor M Spijkers
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.,Mimetas B.V., Organ-on-a-chip Company, Leiden, The Netherlands
| | - Svetlana Pasteuning-Vuhman
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
| | - Paul Vulto
- Mimetas B.V., Organ-on-a-chip Company, Leiden, The Netherlands
| | - R Jeroen Pasterkamp
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
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38
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Van Hook MJ, Monaco C, Bierlein ER, Smith JC. Neuronal and Synaptic Plasticity in the Visual Thalamus in Mouse Models of Glaucoma. Front Cell Neurosci 2021; 14:626056. [PMID: 33584206 PMCID: PMC7873902 DOI: 10.3389/fncel.2020.626056] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 12/21/2020] [Indexed: 11/20/2022] Open
Abstract
Homeostatic plasticity plays important role in regulating synaptic and intrinsic neuronal function to stabilize output following perturbations to circuit activity. In glaucoma, a neurodegenerative disease of the visual system commonly associated with elevated intraocular pressure (IOP), the early disease is associated with altered synaptic inputs to retinal ganglion cells (RGCs), changes in RGC intrinsic excitability, and deficits in optic nerve transport and energy metabolism. These early functional changes can precede RGC degeneration and are likely to alter RGC outputs to their target structures in the brain and thereby trigger homeostatic changes in synaptic and neuronal properties in those brain regions. In this study, we sought to determine whether and how neuronal and synaptic function is altered in the dorsal lateral geniculate nucleus (dLGN), an important RGC projection target in the thalamus, and how functional changes related to IOP. We accomplished this using patch-clamp recordings from thalamocortical (TC) relay neurons in the dLGN in two established mouse models of glaucoma—the DBA/2J (D2) genetic mouse model and an inducible glaucoma model with intracameral microbead injections to elevate IOP. We found that the intrinsic excitability of TC neurons was enhanced in D2 mice and these functional changes were mirrored in recordings of TC neurons from microbead-injected mice. Notably, many neuronal properties were correlated with IOP in older D2 mice, when IOP rises. The frequency of miniature excitatory synaptic currents (mEPSCs) was reduced in 9-month-old D2 mice, and vGlut2 staining of RGC synaptic terminals was reduced in an IOP-dependent manner. These data suggest that glaucoma-associated changes to neuronal excitability and synaptic inputs in the dLGN might represent a combination of both stabilizing/homeostatic plasticity and pathological dysfunction.
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Affiliation(s)
- Matthew J Van Hook
- Department of Ophthalmology and Visual Sciences, Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, United States.,Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Corrine Monaco
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States.,Department of Obstetrics and Gynecology, Olson Center for Women's Health, University of Nebraska Medical Center, Omaha, NE, United States
| | - Elizabeth R Bierlein
- Department of Ophthalmology and Visual Sciences, Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, United States.,Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States
| | - Jennie C Smith
- Department of Ophthalmology and Visual Sciences, Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, United States
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39
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Abnormalities of synaptic mitochondria in autism spectrum disorder and related neurodevelopmental disorders. J Mol Med (Berl) 2020; 99:161-178. [PMID: 33340060 PMCID: PMC7819932 DOI: 10.1007/s00109-020-02018-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 11/27/2020] [Accepted: 12/02/2020] [Indexed: 12/18/2022]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental condition primarily characterized by an impairment of social interaction combined with the occurrence of repetitive behaviors. ASD starts in childhood and prevails across the lifespan. The variability of its clinical presentation renders early diagnosis difficult. Mutations in synaptic genes and alterations of mitochondrial functions are considered important underlying pathogenic factors, but it is obvious that we are far from a comprehensive understanding of ASD pathophysiology. At the synapse, mitochondria perform diverse functions, which are clearly not limited to their classical role as energy providers. Here, we review the current knowledge about mitochondria at the synapse and summarize the mitochondrial disturbances found in mouse models of ASD and other ASD-related neurodevelopmental disorders, like DiGeorge syndrome, Rett syndrome, Tuberous sclerosis complex, and Down syndrome.
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40
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Kwan V, Rosa E, Xing S, Murtaza N, Singh K, Holzapfel NT, Berg T, Lu Y, Singh KK. Proteomic Analysis Reveals Autism-Associated Gene DIXDC1 Regulates Proteins Associated with Mitochondrial Organization and Function. J Proteome Res 2020; 20:1052-1062. [PMID: 33337894 DOI: 10.1021/acs.jproteome.0c00896] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
DIX-domain containing 1 (Dixdc1) is an important regulator of neuronal development including cortical neurogenesis, neuronal migration and synaptic connectivity, and sequence variants in the gene have been linked to autism spectrum disorders (ASDs). Previous studies indicate that Dixdc1 controls neurogenesis through Wnt signaling, whereas its regulation of dendrite and synapse development requires Wnt and cytoskeletal signaling. However, the prediction of these signaling pathways is primarily based on the structure of Dixdc1. Given the role of Dixdc1 in neural development and brain disorders, we hypothesized that Dixdc1 may regulate additional signaling pathways in the brain. We performed transcriptomic and proteomic analyses of Dixdc1 KO mouse cortices to reveal such alterations. We found that transcriptomic approaches do not yield any novel findings about the downstream impacts of Dixdc1. In comparison, our proteomic approach reveals that several important mitochondrial proteins are significantly dysregulated in the absence of Dixdc1, suggesting a novel function of Dixdc1.
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Affiliation(s)
- Vickie Kwan
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4K1, Canada
| | - Elyse Rosa
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4K1, Canada
| | - Sansi Xing
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4K1, Canada
| | - Nadeem Murtaza
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4K1, Canada
| | - Kanwaldeep Singh
- Department of Oncology, McMaster University, Hamilton, Ontario, L8S 4K1, Canada
| | - Nicholas T Holzapfel
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4K1, Canada
| | - Tobias Berg
- Department of Oncology, McMaster University, Hamilton, Ontario, L8S 4K1, Canada
| | - Yu Lu
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4K1, Canada
| | - Karun K Singh
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4K1, Canada.,Krembil Research Institute, University Health Network, Toronto, Ontario, M5T 1S8, Canada.,Faculty of Medicine, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
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41
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Gauba E, Sui S, Tian J, Driskill C, Jia K, Yu C, Rughwani T, Wang Q, Kroener S, Guo L, Du H. Modulation of OSCP mitigates mitochondrial and synaptic deficits in a mouse model of Alzheimer's pathology. Neurobiol Aging 2020; 98:63-77. [PMID: 33254080 DOI: 10.1016/j.neurobiolaging.2020.09.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 09/09/2020] [Accepted: 09/21/2020] [Indexed: 01/22/2023]
Abstract
Synaptic failure underlies cognitive impairment in Alzheimer's disease (AD). Cumulative evidence suggests a strong link between mitochondrial dysfunction and synaptic deficits in AD. We previously found that oligomycin-sensitivity-conferring protein (OSCP) dysfunction produces pronounced neuronal mitochondrial defects in AD brains and a mouse model of AD pathology (5xFAD mice). Here, we prevented OSCP dysfunction by overexpressing OSCP in 5xFAD mouse neurons in vivo (Thy-1 OSCP/5xFAD mice). This approach protected OSCP expression and reduced interaction of amyloid-beta (Aβ) with membrane-bound OSCP. OSCP overexpression also alleviated F1Fo ATP synthase deregulation and preserved mitochondrial function. Moreover, OSCP modulation conferred resistance to Aβ-mediated defects in axonal mitochondrial dynamics and motility. Consistent with preserved neuronal mitochondrial function, OSCP overexpression ameliorated synaptic injury in 5xFAD mice as demonstrated by preserved synaptic density, reduced complement-dependent synapse elimination, and improved synaptic transmission, leading to preserved spatial learning and memory. Taken together, our findings show the consequences of OSCP dysfunction in the development of synaptic stress in AD-related conditions and implicate OSCP modulation as a potential therapeutic strategy.
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Affiliation(s)
- Esha Gauba
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Shaomei Sui
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Jing Tian
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Christopher Driskill
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Kun Jia
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Chunxiao Yu
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Tripta Rughwani
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Qi Wang
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Sven Kroener
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Lan Guo
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA; Department of Pharmacology & Toxicology, The University of Kansas, Lawrence, KS, USA; Higuchi Biosciences Center, The University of Kansas, Lawrence, KS, USA.
| | - Heng Du
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA; Department of Pharmacology & Toxicology, The University of Kansas, Lawrence, KS, USA; Higuchi Biosciences Center, The University of Kansas, Lawrence, KS, USA.
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42
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Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, Hurst C, Glass JD, Factor SA, Johnson ECB, Hajjar I, Lah JJ, Levey AI, Seyfried NT. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer's disease. SCIENCE ADVANCES 2020; 6:eaaz9360. [PMID: 33087358 PMCID: PMC7577712 DOI: 10.1126/sciadv.aaz9360] [Citation(s) in RCA: 224] [Impact Index Per Article: 44.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 09/03/2020] [Indexed: 05/02/2023]
Abstract
Alzheimer's disease (AD) lacks protein biomarkers reflective of its diverse underlying pathophysiology, hindering diagnostic and therapeutic advancements. Here, we used integrative proteomics to identify cerebrospinal fluid (CSF) biomarkers representing a wide spectrum of AD pathophysiology. Multiplex mass spectrometry identified ~3500 and ~12,000 proteins in AD CSF and brain, respectively. Network analysis of the brain proteome resolved 44 biologically diverse modules, 15 of which overlapped with the CSF proteome. CSF AD markers in these overlapping modules were collapsed into five protein panels representing distinct pathophysiological processes. Synaptic and metabolic panels were decreased in AD brain but increased in CSF, while glial-enriched myelination and immunity panels were increased in brain and CSF. The consistency and disease specificity of panel changes were confirmed in >500 additional CSF samples. These panels also identified biological subpopulations within asymptomatic AD. Overall, these results are a promising step toward a network-based biomarker tool for AD clinical applications.
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Affiliation(s)
- Lenora Higginbotham
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA
- Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, GA, USA
| | - Lingyan Ping
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA
- Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, GA, USA
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
| | - Eric B Dammer
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA
- Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, GA, USA
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
| | - Duc M Duong
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA
- Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, GA, USA
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
| | - Maotian Zhou
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA
- Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, GA, USA
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
| | - Marla Gearing
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
- Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, GA, USA
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Cheyenne Hurst
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA
| | - Jonathan D Glass
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA
- Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, GA, USA
| | - Stewart A Factor
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
| | - Erik C B Johnson
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA
- Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, GA, USA
| | - Ihab Hajjar
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
- Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, GA, USA
| | - James J Lah
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA
- Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, GA, USA
| | - Allan I Levey
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA
- Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, GA, USA
| | - Nicholas T Seyfried
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA
- Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, GA, USA
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
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Zhao H, Wang T. PE homeostasis rebalanced through mitochondria-ER lipid exchange prevents retinal degeneration in Drosophila. PLoS Genet 2020; 16:e1009070. [PMID: 33064773 PMCID: PMC7592913 DOI: 10.1371/journal.pgen.1009070] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 10/28/2020] [Accepted: 08/21/2020] [Indexed: 02/06/2023] Open
Abstract
The major glycerophospholipid phosphatidylethanolamine (PE) in the nervous system is essential for neural development and function. There are two major PE synthesis pathways, the CDP-ethanolamine pathway in the endoplasmic reticulum (ER) and the phosphatidylserine decarboxylase (PSD) pathway in mitochondria. However, the role played by mitochondrial PE synthesis in maintaining cellular PE homeostasis is unknown. Here, we show that Drosophila pect (phosphoethanolamine cytidylyltransferase) mutants lacking the CDP-ethanolamine pathway, exhibited alterations in phospholipid composition, defective phototransduction, and retinal degeneration. Induction of the PSD pathway fully restored levels and composition of cellular PE, thus rescued the retinal degeneration and defective visual responses in pect mutants. Disrupting lipid exchange between mitochondria and ER blocked the ability of PSD to rescue pect mutant phenotypes. These findings provide direct evidence that the synthesis of PE in mitochondria contributes to cellular PE homeostasis, and suggest the induction of mitochondrial PE synthesis as a promising therapeutic approach for disorders associated with PE deficiency.
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Affiliation(s)
- Haifang Zhao
- National Institute of Biological Sciences, Beijing, China
| | - Tao Wang
- National Institute of Biological Sciences, Beijing, China
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
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Fourneau J, Cieniewski-Bernard C, Canu MH, Duban-Deweer S, Hachani J, Bastide B, Dupont E. Optimization of 2-DE and multiplexed detection of O-GlcNAcome, phosphoproteome and whole proteome protocol of synapse-associated proteins within the rat sensorimotor cortex. J Neurosci Methods 2020; 343:108807. [DOI: 10.1016/j.jneumeth.2020.108807] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 06/08/2020] [Accepted: 06/11/2020] [Indexed: 11/28/2022]
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Mechanisms and roles of mitochondrial localisation and dynamics in neuronal function. Neuronal Signal 2020; 4:NS20200008. [PMID: 32714603 PMCID: PMC7373250 DOI: 10.1042/ns20200008] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 05/14/2020] [Accepted: 05/15/2020] [Indexed: 01/23/2023] Open
Abstract
Neurons are highly polarised, complex and incredibly energy intensive cells, and their demand for ATP during neuronal transmission is primarily met by oxidative phosphorylation by mitochondria. Thus, maintaining the health and efficient function of mitochondria is vital for neuronal integrity, viability and synaptic activity. Mitochondria do not exist in isolation, but constantly undergo cycles of fusion and fission, and are actively transported around the neuron to sites of high energy demand. Intriguingly, axonal and dendritic mitochondria exhibit different morphologies. In axons mitochondria are small and sparse whereas in dendrites they are larger and more densely packed. The transport mechanisms and mitochondrial dynamics that underlie these differences, and their functional implications, have been the focus of concerted investigation. Moreover, it is now clear that deficiencies in mitochondrial dynamics can be a primary factor in many neurodegenerative diseases. Here, we review the role that mitochondrial dynamics play in neuronal function, how these processes support synaptic transmission and how mitochondrial dysfunction is implicated in neurodegenerative disease.
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Balasubramanian N, Srivastava A, Pawar N, Sagarkar S, Sakharkar AJ. Repeated mild traumatic brain injury induces persistent variations in mitochondrial DNA copy number in mesocorticolimbic neurocircuitry of the rat. Neurosci Res 2020; 155:34-42. [DOI: 10.1016/j.neures.2019.06.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 06/26/2019] [Accepted: 06/27/2019] [Indexed: 12/18/2022]
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Hill RL, Singh IN, Wang JA, Kulbe JR, Hall ED. Protective effects of phenelzine administration on synaptic and non-synaptic cortical mitochondrial function and lipid peroxidation-mediated oxidative damage following TBI in young adult male rats. Exp Neurol 2020; 330:113322. [PMID: 32325157 DOI: 10.1016/j.expneurol.2020.113322] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 04/13/2020] [Accepted: 04/17/2020] [Indexed: 12/11/2022]
Abstract
Traumatic brain injury (TBI) results in mitochondrial dysfunction and induction of lipid peroxidation (LP). Lipid peroxidation-derived neurotoxic aldehydes such as 4-HNE and acrolein bind to mitochondrial proteins, inducing additional oxidative damage and further exacerbating mitochondrial dysfunction and LP. Mitochondria are heterogeneous, consisting of both synaptic and non-synaptic populations, with synaptic mitochondria being more vulnerable to injury-dependent consequences. The goal of these studies was to explore the hypothesis that interrupting secondary oxidative damage following TBI using phenelzine (PZ), an aldehyde scavenger, would preferentially protect synaptic mitochondria against LP-mediated damage in a dose- and time-dependent manner. Male Sprague-Dawley rats received a severe (2.2 mm) controlled cortical impact (CCI)-TBI. PZ (3-30 mg/kg) was administered subcutaneously (subQ) at different times post-injury. We found PZ treatment preserves both synaptic and non-synaptic mitochondrial bioenergetics at 24 h and that this protection is partially maintained out to 72 h post-injury using various dosing regimens. The results from these studies indicate that the therapeutic window for the first dose of PZ is likely within the first hour after injury, and the window for administration of the second dose seems to fall between 12 and 24 h. Administration of PZ was able to significantly improve mitochondrial respiration compared to vehicle-treated animals across various states of respiration for both the non-synaptic and synaptic mitochondria. The synaptic mitochondria appear to respond more robustly to PZ treatment than the non-synaptic, and further experimentation will need to be done to further understand these effects in the context of TBI.
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Affiliation(s)
- Rachel L Hill
- University of Kentucky, Spinal Cord and Brain Injury Research Center (SCoBIRC), United States of America.
| | - Indrapal N Singh
- University of Kentucky, Spinal Cord and Brain Injury Research Center (SCoBIRC), United States of America; Department of Neuroscience, 741 S. Limestone St, Lexington, KY 40536-0509, United States of America
| | - Juan A Wang
- University of Kentucky, Spinal Cord and Brain Injury Research Center (SCoBIRC), United States of America
| | - Jacqueline R Kulbe
- University of Kentucky, Spinal Cord and Brain Injury Research Center (SCoBIRC), United States of America
| | - Edward D Hall
- University of Kentucky, Spinal Cord and Brain Injury Research Center (SCoBIRC), United States of America; Department of Neuroscience, 741 S. Limestone St, Lexington, KY 40536-0509, United States of America
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Kumar A. Calcium Signaling During Brain Aging and Its Influence on the Hippocampal Synaptic Plasticity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1131:985-1012. [PMID: 31646542 DOI: 10.1007/978-3-030-12457-1_39] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Calcium (Ca2+) ions are highly versatile intracellular signaling molecules and are universal second messenger for regulating a variety of cellular and physiological functions including synaptic plasticity. Ca2+ homeostasis in the central nervous system endures subtle dysregulation with advancing age. Research has provided abundant evidence that brain aging is associated with altered neuronal Ca2+ regulation and synaptic plasticity mechanisms. Much of the work has focused on the hippocampus, a brain region critically involved in learning and memory, which is particularly susceptible to dysfunction during aging. The current chapter takes a specific perspective, assessing various Ca2+ sources and the influence of aging on Ca2+ sources and synaptic plasticity in the hippocampus. Integrating the knowledge of the complexity of age-related alterations in neuronal Ca2+ signaling and synaptic plasticity mechanisms will positively shape the development of highly effective therapeutics to treat brain disorders including cognitive impairment associated with aging and neurodegenerative disease.
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Affiliation(s)
- Ashok Kumar
- Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
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Abstract
Isolated mitochondria are useful to study fundamental processes including mitochondrial respiration, metabolic activity, protein import, membrane fusion, protein complex assembly, as well as interactions of mitochondria with the cytoskeleton, nuclear encoded mRNAs, and other organelles. In addition, studies of the mitochondrial proteome, phosphoproteome, and lipidome are dependent on preparation of highly purified mitochondria (Boldogh, Vojtov, Karmon, & Pon, 1998; Cui, Conte, Fox, Zara, & Winge, 2014; Marc et al., 2002; Meeusen, McCaffery, & Nunnari, 2004; Reinders et al., 2007; Schneiter et al., 1999; Stuart & Koehler, 2007). Most methods to isolate mitochondria rely on differential centrifugation, a two-step centrifugation carried out at low speed to remove intact cells, cell and tissue debris, and nuclei from whole cell extracts followed by high speed centrifugation to concentrate mitochondria and separate them from other organelles. However, methods to disrupt cells and tissue vary. Moreover, density gradient centrifugation or affinity purification of the organelle are used to further purify mitochondria or to separate different populations of the organelle. Here, we describe protocols to isolate mitochondria from different cells and tissues as well as approaches to assess the purity and integrity of isolated organelles.
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50
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Sabharwal V, Koushika SP. Crowd Control: Effects of Physical Crowding on Cargo Movement in Healthy and Diseased Neurons. Front Cell Neurosci 2019; 13:470. [PMID: 31708745 PMCID: PMC6823667 DOI: 10.3389/fncel.2019.00470] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Accepted: 10/02/2019] [Indexed: 01/22/2023] Open
Abstract
High concentration of cytoskeletal filaments, organelles, and proteins along with the space constraints due to the axon's narrow geometry lead inevitably to intracellular physical crowding along the axon of a neuron. Local cargo movement is essential for maintaining steady cargo transport in the axon, and this may be impeded by physical crowding. Molecular motors that mediate active transport share movement mechanisms that allow them to bypass physical crowding present on microtubule tracks. Many neurodegenerative diseases, irrespective of how they are initiated, show increased physical crowding owing to the greater number of stalled organelles and structural changes associated with the cytoskeleton. Increased physical crowding may be a significant factor in slowing cargo transport to synapses, contributing to disease progression and culminating in the dying back of the neuronal process. This review explores the idea that physical crowding can impede cargo movement along the neuronal process. We examine the sources of physical crowding and strategies used by molecular motors that might enable cargo to circumvent physically crowded locations. Finally, we describe sub-cellular changes in neurodegenerative diseases that may alter physical crowding and discuss the implications of such changes on cargo movement.
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Affiliation(s)
| | - Sandhya P. Koushika
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
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