ArticleCell communication and signaling : CCS2023
Defective quality control autophagy in Hyperhomocysteinemia promotes ER stress and consequent neuronal apoptosis through proteotoxicity.
Article in Cell communication and signaling : CCS, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 20 citations in OpenAlex.
- Article
- Trimethylamine N-oxide and Homocysteine in Kidney Function and Disease: Distinct Metabolic Origins, Shared Renal Determinants and Pathophysiological Pathways.International journal of molecular sciences · 2026Review
- Article
- Betaine Attenuates Hyperhomocysteinemia-Induced Cognitive Impairment by Suppressing Oxidative Stress and Activating the PI3K/AKT/GSK-3β Pathway.Antioxidants (Basel, Switzerland) · 2026Article
- Accelerated epigenetic aging as a modifier of homocysteine-associated cognitive decline: Findings from NHANES.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- H-type hypertension and U-shaped body mass index predict atrial fibrillation recurrence after catheter ablation: Insights from a 3-year follow-up.Heart rhythm O2 · 2025Article
- Homocysteinylation of Fibrinogen: A Post-Translational Link to Thrombosis.International journal of molecular sciences · 2025Review
- The tumor-promoting role of methionyl-tRNA synthetase 1 in ovarian cancer and its potential mechanisms.Medical oncology (Northwood, London, England) · 2025Article
- Structural basis for the inhibition of cystathionine-β-synthase by isoflurane and its role in anaesthesia-induced social dysfunction in mice.British journal of anaesthesia · 2025Article
- An update on autophagy disorders.Journal of inherited metabolic disease · 2025Review
- Chronic Hyperhomocysteinemia Impairs CSD Propagation and Induces Cortical Damage in a Rat Model of Migraine with Aura.Biomolecules · 2024Article
- Enhancing Differential Diagnosis Related to Oxidative Stress, Nitrous Oxide, and Nutrition by Rapid Plasma Homocysteine Measurement.Journal of xenobiotics · 2024Article
- Cellular turnover and degradation of the most common missense cystathionine beta-synthase variants causing homocystinuria.Protein science : a publication of the Protein Society · 2024Article
- Obstructive sleep apnea affects cognition: dual effects of intermittent hypoxia on neurons.Sleep & breathing = Schlaf & Atmung · 2024Review
- Article
- The role of mitophagy in metabolic diseases and its exercise intervention.Frontiers in physiology · 2024Review
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Homocysteine (Hcy), produced physiologically in all cells, is an intermediate metabolite of methionine and cysteine metabolism. Hyperhomocysteinemia (HHcy) resulting from an in-born error of metabolism that leads to accumulation of high levels of Hcy, is associated with vascular damage, neurodegeneration and cognitive decline. Using a HHcy model in neuronal cells, primary cortical neurons and transgenic zebrafish, we demonstrate diminished autophagy and Hcy-induced neurotoxicity associated with mitochondrial dysfunction, fragmentation and apoptosis. We find this mitochondrial dysfunction is due to Hcy-induced proteotoxicity leading to ER stress. We show this sustained proteotoxicity originates from the perturbation of upstream autophagic pathways through an aberrant activation of mTOR and that protetoxic stress act as a feedforward cues to aggravate a sustained ER stress that culminate to mitochondrial apoptosis in HHcy model systems. Using chemical chaperones to mitigate sustained ER stress, Hcy-induced proteotoxicity and consequent neurotoxicity were rescued. We also rescue neuronal lethality by activation of autophagy and thereby reducing proteotoxicity and ER stress. Our findings pave the way to devise new strategies for the treatment of neural and cognitive pathologies reported in HHcy, by either activation of upstream autophagy or by suppression of downstream ER stress. Video Abstract.
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