ArticleActa neuropathologica communications2020
Mitochondrial defects in the respiratory complex I contribute to impaired translational initiation via ROS and energy homeostasis in SMA motor neurons.
Article in Acta neuropathologica communications, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 45 citations in OpenAlex.
- Organ-specific redox imbalances in spinal muscular atrophy mice are partially rescued by SMN antisense oligonucleotides.FEBS letters · 2026Article
- Pharmacological Activation of NRF2 by Omaveloxolone Upregulates NRF2-Target Proteins in SMA Type I Human Fibroblasts.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- miR-423-5p/NDUFS7-mediated mitochondrial function modulation contributes to quercetin-induced attenuation of pulmonary fibrosis via extracellular matrix remodeling regulation.Non-coding RNA research · 2026Article
- Mitochondrial Dysfunction Associated with mtDNA Mutation: Mitochondrial Genome Editing in Atherosclerosis Research.Current medicinal chemistry · 2026Article
- Mitochondria-Associated Membrane Dysfunction in Neurodegeneration and Its Effects on Lipid Metabolism, Calcium Signaling, and Cell Fate.Membranes · 2025Review
- Blueprint of Collapse: Precision Biomarkers, Molecular Cascades, and the Engineered Decline of Fast-Progressing ALS.International journal of molecular sciences · 2025Review
- Efficacy of Mitochondrial Transfer in Healing Toxin-Induced Damage to Neuromuscular Junction, an Empirical Study.Synapse (New York, N.Y.) · 2025Article
- Glial Cells in Spinal Muscular Atrophy: Speculations on Non-Cell-Autonomous Mechanisms and Therapeutic Implications.Neurology international · 2025Review
- Genetic Variability in Oxidative Stress, Inflammatory, and Neurodevelopmental Pathways: Impact on the Susceptibility and Course of Spinal Muscular Atrophy.Cellular and molecular neurobiology · 2024Article
- Characterization of SMA type II skeletal muscle from treated patients shows OXPHOS deficiency and denervation.JCI insight · 2024Article
- CLUH maintains functional mitochondria and translation in motoneuronal axons and prevents peripheral neuropathy.Science advances · 2024Article
- A Consolidated Understanding of the Contribution of Redox Dysregulation in the Development of Hearing Impairment.Antioxidants (Basel, Switzerland) · 2024Review
- The SMN-ribosome interplay: a new opportunity for Spinal Muscular Atrophy therapies.Biochemical Society transactions · 2024Review
- A transcriptomics-based drug repositioning approach to identify drugs with similar activities for the treatment of muscle pathologies in spinal muscular atrophy (SMA) models.Human molecular genetics · 2024Article
- Mitochondrial Inherited Disorders and their Correlation with Neurodegenerative Diseases.Endocrine, metabolic & immune disorders drug targets · 2024Review
- AAV9-mediated SMN gene therapy rescues cardiac desmin but not lamin A/C and elastin dysregulation in Smn2B/- spinal muscular atrophy mice.Human molecular genetics · 2023Article
- Mitochondrial heterogeneity in diseases.Signal transduction and targeted therapy · 2023Review
- Redox Imbalance in Neurological Disorders in Adults and Children.Antioxidants (Basel, Switzerland) · 2023Review
- CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD.Brain : a journal of neurology · 2023Article
- NADPH oxidase 4 inhibition is a complementary therapeutic strategy for spinal muscular atrophy.Frontiers in cellular neuroscience · 2023Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by loss of lower motor neurons, which leads to proximal muscle weakness and atrophy. SMA is caused by reduced survival motor neuron (SMN) protein levels due to biallelic deletions or mutations in the SMN1 gene. When SMN levels fall under a certain threshold, a plethora of cellular pathways are disturbed, including RNA processing, protein synthesis, metabolic defects, and mitochondrial function. Dysfunctional mitochondria can harm cells by decreased ATP production and increased oxidative stress due to elevated cellular levels of reactive oxygen species (ROS). Since neurons mainly produce energy via mitochondrial oxidative phosphorylation, restoring metabolic/oxidative homeostasis might rescue SMA pathology. Here, we report, based on proteome analysis, that SMA motor neurons show disturbed energy homeostasis due to dysfunction of mitochondrial complex I. This results in a lower basal ATP concentration and higher ROS production that causes an increase of protein carbonylation and impaired protein synthesis in SMA motor neurons. Counteracting these cellular impairments with pyruvate reduces elevated ROS levels, increases ATP and SMN protein levels in SMA motor neurons. Furthermore, we found that pyruvate-mediated SMN protein synthesis is mTOR-dependent. Most importantly, we showed that ROS regulates protein synthesis at the translational initiation step, which is impaired in SMA. As many neuropathies share pathological phenotypes such as dysfunctional mitochondria, excessive ROS, and impaired protein synthesis, our findings suggest new molecular interactions among these pathways. Additionally, counteracting these impairments by reducing ROS and increasing ATP might be beneficial for motor neuron survival in SMA patients.
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