ArticleHuman molecular genetics2021
Multi-OMICS study of a CHCHD10 variant causing ALS demonstrates metabolic rewiring and activation of endoplasmic reticulum and mitochondrial unfolded protein responses.
Article in Human molecular genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers, 1 of them a synthesis that pooled it.
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Who cites it
42 citing papers in PubMed, 1 synthesis or guideline pooled it, 65 citations in OpenAlex.
- A systematic review of the neuroprotective role and biomarker potential of GDF15 in neurodegeneration.Frontiers in immunology · 2024Pooled it
- N-of-1 investigational study of a novel antisense oligonucleotide drug in CHCHD10-related ALS shows early signs of efficacy.Med (New York, N.Y.) · 2026Article
- Mitochondrial dysfunction triggers a maladaptive peroxisomal response driving lipid accumulation.Redox biology · 2026Article
- Neuromuscular junction innervation and motor function are preserved by restoring muscarinic signaling in perisynaptic glia in ALS.iScience · 2026Article
- Mechanistic insights and therapeutic interventions of mitochondrial quality control in chemotherapy-related cognitive impairment.Neoplasia (New York, N.Y.) · 2026Review
- Amyloid fibril structures link CHCHD10 and CHCHD2 to neurodegeneration.Nature communications · 2025Article
- Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism.Acta neuropathologica communications · 2025Article
- Mipep deficiency in adipocytes impairs mitochondrial protein maturation and leads to systemic inflammation and metabolic dysfunctions.Scientific reports · 2025Article
- Review: Utility of mass spectrometry in rare disease research and diagnosis.NPJ genomic medicine · 2025Review
- Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models.Nature communications · 2025Article
- Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation.Biomolecules · 2024Article
- m6A RNA methylation regulates mitochondrial function.Human molecular genetics · 2024Article
- The Role of SLIT3-ROBO4 Signaling in Endoplasmic Reticulum Stress-Induced Delayed Corneal Epithelial and Nerve Regeneration.Investigative ophthalmology & visual science · 2024Article
- Enhancement of Mitochondrial Homeostasis: A Novel Approach to Attenuate Hypoxic Myocardial Injury.International journal of medical sciences · 2024Review
- Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.Biomolecules · 2023Review
- Review
- Ferroptosis and Neurodegenerative Diseases: Insights into the Regulatory Roles of SLC7A11.Cellular and molecular neurobiology · 2023Review
- Review
- Natural Drugs: A New Direction for the Prevention and Treatment of Diabetes.Molecules (Basel, Switzerland) · 2023Review
- mtUPR Modulation as a Therapeutic Target for Primary and Secondary Mitochondrial Diseases.International journal of molecular sciences · 2023Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
Mutations in CHCHD10, coding for a mitochondrial intermembrane space protein, are a rare cause of autosomal dominant amyotrophic lateral sclerosis. Mutation-specific toxic gain of function or haploinsufficiency models have been proposed to explain pathogenicity. To decipher the metabolic dysfunction associated with the haploinsufficient p.R15L variant, we integrated transcriptomic, metabolomic and proteomic data sets in patient cells subjected to an energetic stress that forces the cells to rely on oxidative phosphorylation for ATP production. Patient cells had a complex I deficiency that resulted in an increased NADH/NAD+ ratio, diminished TCA cycle activity, a reorganization of one carbon metabolism and an increased AMP/ATP ratio leading to phosphorylation of AMPK and inhibition of mTORC1. These metabolic changes activated the unfolded protein response (UPR) in the ER through the IRE1/XBP1 pathway, upregulating downstream targets including ATF3, ATF4, CHOP and EGLN3, and two cytokine markers of mitochondrial disease, GDF15 and FGF21. Activation of the mitochondrial UPR was mediated through an upregulation of the transcription factors ATF4 and ATF5, leading to increased expression of mitochondrial proteases and heat shock proteins. There was a striking transcriptional up regulation of at least seven dual specific phosphatases, associated with an almost complete dephosphorylation of JNK isoforms, suggesting a concerted deactivation of MAP kinase pathways. This study demonstrates that loss of CHCHD10 function elicits an energy deficit that activates unique responses to nutrient stress in both the mitochondria and ER, which may contribute to the selective vulnerability of motor neurons.
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Registered trials
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