ArticleThe Journal of biological chemistry2017
Regulation of mitochondrial protein import by the nucleotide exchange factors GrpEL1 and GrpEL2 in human cells.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 62 citations in OpenAlex.
- Beyond the obvious pocket.Nature chemical biology · 2026Article
- Tryptoline stereoprobe elaboration identifies inhibitors of the GRPEL1-HSPA9 complex.Nature chemical biology · 2026Article
- Regulation of cellular proteostasis via mitochondrial protein import.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Review
- Inference of upstream-mutation and metabolomic-signature causality identifies prognostic biomarkers and therapeutic targets in pancreatic cancer.Nature communications · 2026Article
- Rearrangement of the Cell Chaperone Machinery in Human Fibrosarcoma HT1080 Cells With the Knocked-Out HSP90AA1 Gene Encoding Hsp90α.Biology of the cell · 2026Article
- Tuning the Hsp70 chaperone cycle: emerging roles of GrpE-like nucleotide exchange factors in proteostasis and organelle function.Protein & cell · 2026Review
- Mechanisms and regulation of the Hsp70 chaperone network.Nature reviews. Molecular cell biology · 2026Review
- Article
- Vincristine Treatment Protects Against Podocyte Damage in Focal Segmental Glomerulosclerosis.Kidney international reports · 2025Article
- Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations.Signal transduction and targeted therapy · 2025Review
- Tryptoline Stereoprobe Elaboration Identifies Inhibitors of the GRPEL1-HSPA9 Chaperone Complex.bioRxiv : the preprint server for biology · 2025Article
- E2F8-induced GRPEL2 promoted colorectal cancer progression via targeting TIGAR.Journal of translational medicine · 2025Article
- Structural insights into GrpEL1-mediated nucleotide and substrate release of human mitochondrial Hsp70.Nature communications · 2024Article
- Preferential binding of ADP-bound mitochondrial HSP70 to the nucleotide exchange factor GRPEL1 over GRPEL2.Protein science : a publication of the Protein Society · 2024Article
- Thrombocytopenia in dengue infection: mechanisms and a potential application.Expert reviews in molecular medicine · 2024Review
- Structural insights into GrpEL1-mediated nucleotide and substrate release of human mitochondrial Hsp70.bioRxiv : the preprint server for biology · 2024Article
- Causal Relationship between Mitochondrial-Associated Proteins and Sepsis in ICU Patients: A Mendelian Randomization Study.ACS omega · 2024Article
- Translation Fidelity and Respiration Deficits in CLPP-Deficient Tissues: Mechanistic Insights from Mitochondrial Complexome Profiling.International journal of molecular sciences · 2023Article
- Mitochondrial dysfunction rapidly modulates the abundance and thermal stability of cellular proteins.Life science alliance · 2023Article
- Grpel2 maintains cardiomyocyte survival in diabetic cardiomyopathy through DLST-mediated mitochondrial dysfunction: a proof-of-concept study.Journal of translational medicine · 2023Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mitochondria are organelles indispensable for maintenance of cellular energy homeostasis. Most mitochondrial proteins are nuclearly encoded and are imported into the matrix compartment where they are properly folded. This process is facilitated by the mitochondrial heat shock protein 70 (mtHsp70), a chaperone contributing to mitochondrial protein quality control. The affinity of mtHsp70 for its protein clients and its chaperone function are regulated by binding of ATP/ADP to mtHsp70's nucleotide-binding domain. Nucleotide exchange factors (NEFs) play a crucial role in exchanging ADP for ATP at mtHsp70's nucleotide-binding domain, thereby modulating mtHsp70's chaperone activity. A single NEF, Mge1, regulates mtHsp70's chaperone activity in lower eukaryotes, but the mammalian orthologs are unknown. Here, we report that two putative NEF orthologs, GrpE-like 1 (GrpEL1) and GrpEL2, modulate mtHsp70's function in human cells. We found that both GrpEL1 and GrpEL2 associate with mtHsp70 as a hetero-oligomeric subcomplex and regulate mtHsp70 function. The formation of this subcomplex was critical for conferring stability to the NEFs, helped fine-tune mitochondrial protein quality control, and regulated crucial mtHsp70 functions, such as import of preproteins and biogenesis of Fe-S clusters. Our results also suggested that GrpEL2 has evolved as a possible stress resistance protein in higher vertebrates to maintain chaperone activity under stress conditions. In conclusion, our findings support the idea that GrpEL1 has a role as a stress modulator in mammalian cells and highlight that multiple NEFs are involved in controlling protein quality in mammalian mitochondria.
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