The HRI branch of the integrated stress response selectively triggers mitophagy

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(6), P. 1090 - 1100.e6

Published: Feb. 9, 2024

To maintain mitochondrial homeostasis, damaged or excessive mitochondria are culled in coordination with the physiological state of cell. The integrated stress response (ISR) is a signaling network that recognizes diverse cellular stresses, including dysfunction. Because four ISR branches converge to common outputs, it unclear whether detected by this can regulate mitophagy, autophagic degradation mitochondria. Using whole-genome screen, we show heme-regulated inhibitor (HRI) branch selectively induces mitophagy. Activation HRI results localization phosphorylated eukaryotic initiation factor 2, which sufficient induce mitophagy pathway operates parallel controlled Parkinson's disease related genes PINK1 and PARKIN mechanistically distinct. Therefore, repurposes machinery normally used for translational trigger damage.

Language: Английский

---

Mapping stress-responsive signaling pathways induced by mitochondrial proteostasis perturbations

Molecular Biology of the Cell, Journal Year: 2024, Volume and Issue: 35(5)

Published: March 27, 2024

Imbalances in mitochondrial proteostasis are associated with pathologic dysfunction implicated etiologically diverse diseases. This has led to considerable interest defining the mechanisms responsible for regulating mitochondria response stress. Numerous stress-responsive signaling pathways have been suggested regulate proteotoxic These include integrated stress (ISR), heat shock (HSR), and oxidative (OSR). Here, we define activated chronic perturbations by monitoring expression of sets genes regulated downstream each these published Perturb-seq datasets from K562 cells CRISPRi-depleted factors. Interestingly, find that ISR is preferentially chronic, genetically-induced stress, no other pathway showing significant activation. Further, demonstrate CRISPRi depletion mitochondria-localized proteins similarly shows preferential activation relative pathways. results both establish our gene set profiling approach as a viable strategy probe responsive induced specific organelles identify predominant disruption proteostasis.

Language: Английский

---

Pharmacologic Activation of Integrated Stress Response Kinases Inhibits Pathologic Mitochondrial Fragmentation

Published: Jan. 16, 2025

Excessive mitochondrial fragmentation is associated with the pathologic dysfunction implicated in pathogenesis of etiologically-diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) – comprising four eIF2α kinases PERK, GCN2, PKR, and HRI a prominent stress-responsive signaling pathway that regulates morphology function to diverse types insult. This suggests pharmacologic activation ISR represents potential strategy mitigate human disease. Here, we show or GCN2 promotes adaptive elongation prevents induced by calcium ionophore ionomycin. Further, reduces restores basal patient fibroblasts expressing pathogenic D414V variant pro-fusion GTPase MFN2 neurological dysfunctions ataxia, optic atrophy, sensorineural hearing loss. These results identify as prevent disease-relevant chemical genetic insults, further motivating pursuit highly selective kinase-activating compounds therapeutic diseases.

Language: Английский

---

Pharmacologic activation of integrated stress response kinases inhibits pathologic mitochondrial fragmentation

eLife, Journal Year: 2025, Volume and Issue: 13

Published: Feb. 12, 2025

Excessive mitochondrial fragmentation is associated with the pathologic dysfunction implicated in pathogenesis of etiologically diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) – comprising four eIF2α kinases PERK, GCN2, PKR, and HRI a prominent stress-responsive signaling pathway that regulates morphology function to types insult. This suggests pharmacologic activation ISR represents potential strategy mitigate human disease. Here, we show or GCN2 promotes adaptive elongation prevents induced by calcium ionophore ionomycin. Further, reduces restores basal patient fibroblasts expressing pathogenic D414V variant pro-fusion GTPase MFN2 neurological dysfunctions, ataxia, optic atrophy, sensorineural hearing loss. These results identify as prevent disease-relevant chemical genetic insults, further motivating pursuit highly selective kinase-activating compounds therapeutic diseases.

Language: Английский

---

The PERK-eIF2α-ATF4 Axis Is Involved in Mediating ER-Stress-Induced Ferroptosis via DDIT4-mTORC1 Inhibition and Acetaminophen-Induced Hepatotoxicity

Antioxidants, Journal Year: 2025, Volume and Issue: 14(3), P. 307 - 307

Published: March 3, 2025

Ferroptosis, a regulated form of cell death characterized by lipid peroxidation and iron accumulation, is increasingly recognized for its role in disease pathogenesis. The unfolded protein response (UPR) has been implicated both endoplasmic reticulum (ER) stress ferroptosis-mediated fate decisions; yet, the specific mechanism remains poorly understood. In this study, we demonstrated that ER induced tunicamycin ferroptosis triggered erastin activate UPR, leading to induction ferroptotic death. This was mitigated application chemical chaperones inhibitor. Among three arms PERK-eIF2α-ATF4 signaling axis identified as crucial mediator process. Mechanistically, ATF4-driven DDIT4 plays pivotal role, facilitating via inhibition mTORC1 pathway. Furthermore, acetaminophen (APAP)-induced hepatotoxicity investigated model eIF2α-ATF4-mediated ferroptosis. Our findings reveal eIF2α-ATF4 or protects against APAP-induced liver damage, underscoring therapeutic potential targeting these pathways. Overall, study not only clarifies intricate ER-stress-and erastin-induced but also extends clinically relevant model, providing foundation interventions conditions dysregulated stress.

Language: Английский

---

Mitochondrial quality control and stress signaling pathways in the pathophysiology of cardio-renal diseases

Mitochondrion, Journal Year: 2025, Volume and Issue: unknown, P. 102040 - 102040

Published: April 1, 2025

Mitochondria are essential organelles for cellular function and have become a broad field of study. In cardio-renal diseases, it has been established that mitochondrial dysfunction is primary mechanism leading to these pathologies. Under stress, mitochondria can develop stress response mechanisms maintain quality control (MQC) functions. contrast, the perturbation associated with pathogenesis several diseases. Thus, targeting specific pathways within MQC could offer therapeutic avenue protecting integrity. However, related signaling in axis poorly explored. The limitations include lack reproducibility experimental models disease, incomplete knowledge molecules generate bidirectional damage, temporality study models. Therefore, we believe integration all those limitations, along recent advances (i.e., mitophagy), (e.g., integrated response, unfolded protein import), pharmacology, targeted approaches reveal what deregulation like provide ideas generating strategies seek avoid progression

Language: Английский

---

Better Together: Interorganellar Communication in the Regulation of Proteostasis

Contact, Journal Year: 2024, Volume and Issue: 7

Published: Jan. 1, 2024

An extensive network of chaperones and folding factors is responsible for maintaining a functional proteome, which the basis cellular life. The underlying proteostatic mechanisms are not isolated within organelles, rather they connected over organellar borders via signalling processes or direct association contact sites. This review aims to provide conceptual understanding across organelle borders, focussing on individual organelles. discussion highlights precision these finely tuned systems, emphasising complicated balance between protection adaptation stress. In this review, we discuss widely accepted aspects while shedding light newly discovered perspectives.

Language: Английский

---

Pharmacologic Activation of Integrated Stress Response Kinases Inhibits Pathologic Mitochondrial Fragmentation

eLife, Journal Year: 2024, Volume and Issue: 13

Published: Sept. 25, 2024

Excessive mitochondrial fragmentation is associated with the pathologic dysfunction implicated in pathogenesis of etiologically diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) - comprising four eIF2α kinases PERK, GCN2, PKR, and HRI a prominent stress-responsive signaling pathway that regulates morphology function to types insult. This suggests pharmacologic activation ISR represents potential strategy mitigate human disease. Here, we show or GCN2 promotes adaptive elongation prevents induced by calcium ionophore ionomycin. Further, reduces restores basal patient fibroblasts expressing pathogenic D414V variant pro-fusion GTPase MFN2 neurological dysfunctions, ataxia, optic atrophy, sensorineural hearing loss. These results identify as prevent disease-relevant chemical genetic insults, further motivating pursuit highly selective kinase-activating compounds therapeutic diseases.

Language: Английский

---

Trimethylamine-N-oxide accelerates osteoporosis by PERK activation of ATF5 unfolding

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 82(1)

Published: Dec. 24, 2024

Imbalances in gut microbiota and their metabolites have been implicated osteoporotic disorders. Trimethylamine-n-oxide (TMAO), a metabolite of L-carnitine produced by microorganisms flavin-containing monooxygenase-3, is known to accelerate tissue metabolism remodeling; however, its role bone loss remained unexplored. This study investigates the relationship between dysbiosis, TMAO production, osteoporosis development. We further demonstrate that beneficial associated with development murine alterations serum metabolome, particularly affecting metabolism. emerges as functional detrimental homeostasis. Notably, transplantation mouse counteracts obesity- or estrogen deficiency-induced overproduction mitigates key features osteoporosis. Mechanistically, excessive intake augments mass inhibiting mineral acquisition osteogenic differentiation. activates PERK ATF4-dependent disruption endoplasmic reticulum autophagy suppresses folding ATF5, hindering mitochondrial unfolding protein response (UPRmt) osteoblasts. Importantly, UPRmt activation nicotinamide riboside TMAO-induced inhibition mineralized matrix biosynthesis preserving oxidative phosphorylation mitophagy. Collectively, our findings revealed dysbiosis leads overproduction, impairing ER homeostasis UPRmt, thereby aggravating osteoblast dysfunction Our elucidates catabolic microflora-derived integrity highlights therapeutic potential healthy donor alter progression

Language: Английский

---

Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 1, 2024

SUMMARY Imbalances in mitochondrial proteostasis are associated with pathologic dysfunction implicated etiologically-diverse diseases. This has led to considerable interest defining the biological mechanisms responsible for regulating mitochondria response stress. Numerous stress responsive signaling pathways have been suggested regulate proteotoxic stress, including integrated (ISR), heat shock (HSR), and oxidative (OSR). Here, we define specific activated by monitoring expression of sets genes regulated downstream each these published Perturb-seq datasets from K562 cells CRISPRi-depleted individual factors. Interestingly, find that ISR is preferentially no other pathway showing significant activation. Further expanding this study, show broad depletion mitochondria-localized proteins similarly shows preferential activation relative stress-responsive pathways. These results both establish our gene set profiling approach as a viable strategy probe induced perturbations organelles identify predominant disruption.

Language: Английский

---