ArticleScience advances2025
Kinome screening identifies integrated stress response kinase EIF2AK1/HRI as a negative regulator of PINK1 mitophagy signaling.
Article in Science advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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Who cites it
8 citing papers in PubMed.
- From Cellular Stress to Systemic Adaptation: The Circadian Clock and Stress Response at Cellular and Systemic Levels.International journal of molecular sciences · 2026Review
- Structural insights into HRI kinase activity and inhibition.Biochemical Society transactions · 2026Review
- Quality control of protein import into mammalian mitochondria.Protein science : a publication of the Protein Society · 2026Review
- The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.Nature communications · 2026Article
- Function and regulation of the mitochondrial stress response.Nature structural & molecular biology · 2026Review
- Targeting the metabolic fingerprint of amino acids to identify novel metabolic characteristics in osteosarcoma patients undergoing anthracycline treatment.Scientific reports · 2026Article
- Putative PINK1/Parkin activators lower the threshold for mitophagy by sensitizing cells to mitochondrial stress.Science advances · 2025Article
- Stressful situations: Molecular insights on mitochondrial quality control pathways.The Journal of biological chemistry · 2025Review
Corrections and comments
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Authors and funding
12 authors.
Funding
Abstract
Loss-of-function mutations in the PINK1 kinase lead to early-onset Parkinson's disease (PD). PINK1 is activated by mitochondrial damage to phosphorylate ubiquitin and Parkin, triggering mitophagy. PINK1 also indirectly phosphorylates Rab GTPases, such as Rab8A. Using an siRNA library targeting human Ser/Thr kinases in HeLa cells, we identified EIF2AK1 [heme-regulated inhibitor (HRI) kinase], a branch of the integrated stress response (ISR), as a negative regulator of PINK1. EIF2AK1 knockdown enhances mitochondrial depolarization-induced PINK1 stabilization and phosphorylation of ubiquitin and Rab8A. These results were confirmed in SK-OV-3, U2OS, and ARPE-19 cells. Knockdown of DELE1, an activator of EIF2AK1, produced similar effects. Notably, the ISR inhibitor ISRIB also enhanced PINK1 activation. In human cells with mito-QC mitophagy reporters, EIF2AK1 knockdown or ISRIB treatment increased PINK1-dependent mitophagy without affecting deferiprone-induced mitophagy. These findings suggest that the DELE1-EIF2AK1 ISR pathway is a negative regulator of PINK1-dependent mitophagy. Further evaluation in PD-relevant models is needed to assess the therapeutic potential of targeting this pathway.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.