The Integrated Stress Response Suppresses PINK1-dependent Mitophagy by Preserving Mitochondrial Import Efficiency DOI
Mingchong Yang,

Zengshuo Mo,

K. J. Walsh

et al.

Published: Oct. 17, 2024

Abstract Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of DELE1-HRI axis integrated response (ISR) in regulating mitophagy, a key pathway. Our findings show that ISR suppresses mitophagy under non-depolarizing by positively protein import, independent ATF4 activation. Mitochondrial import regulated rate synthesis both depolarizing and stress. Without ISR, increased overwhelms machinery, reducing efficiency. Under stress, heavily impaired even with active leading significant PINK1 accumulation. contrast, allows more efficient presence resulting lower mitophagy. becomes severely compromised, causing accumulation reach threshold necessary trigger These reveal novel link between ISR-regulated synthesis, offering potential therapeutic targets diseases associated dysfunction.

Language: Английский

Pharmacologic Activation of Integrated Stress Response Kinases Inhibits Pathologic Mitochondrial Fragmentation DOI Creative Commons
Kelsey R. Baron, Samantha Oviedo,

Sophia Krasny

et al.

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

Published: June 10, 2024

SUMMARY 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

Citations

0
Hemin binding causes structural rearrangements in HRI to inhibit activation via autophosphorylation DOI Creative Commons

Shivani Kanta,

Vanesa Vinciauskaite,

Graham W. Neill

et al.

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

Published: Aug. 14, 2024

Abstract Heme-Regulated Inhibitor (HRI) is one of the four mammalian kinases which phosphorylates eIF2α to facilitate a cellular response stress through regulation mRNA translation. Originally identified for its role as heme sensor in erythroid progenitor cells, it has since materialised potential therapeutic target both cancer and neurodegeneration. Here we characterise two modes HRI inhibition using structural mass spectrometry, biochemical biophysical techniques. We demonstrate that several ATP-mimetic compounds, including BRAF inhibitors compound, GCN2iB, thought be specific GCN2, are capable potently inhibiting HRI. hemin, haem-like molecule, inactivates structurally hydrogen-deuterium exchange spectrometry (HDX-MS), this results wide-spread rearrangement protein how impacts on kinase domain series allosteric interactions. This mainly autophosphorylation, includes tyrosine phosphorylation, not observed before kinases.

Language: Английский

Citations

0
Pharmacologic Activation of Integrated Stress Response Kinases Inhibits Pathologic Mitochondrial Fragmentation DOI Open Access
Kelsey R. Baron, Samantha Oviedo,

Sophia Krasny

et al.

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 diverse types insult. This suggests pharmacologic, stress-independent activation ISR represents potential strategy mitigate human disease. Here, we show or GCN2 promotes adaptive elongation prevents induced by calcium ionophore ionomycin. Further, these 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

Citations

0
CEAM is a mitochondrial-localized, amyloid-like motif-containing microprotein expressed in human cardiomyocytes DOI
Ruobing Li,

Ti Qin,

Yabo Guo

et al.

Biochemical and Biophysical Research Communications, Journal Year: 2024, Volume and Issue: 734, P. 150737 - 150737

Published: Oct. 5, 2024

Language: Английский

Citations

0
The Integrated Stress Response Suppresses PINK1-dependent Mitophagy by Preserving Mitochondrial Import Efficiency DOI
Mingchong Yang,

Zengshuo Mo,

K. J. Walsh

et al.

Published: Oct. 17, 2024

Abstract Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of DELE1-HRI axis integrated response (ISR) in regulating mitophagy, a key pathway. Our findings show that ISR suppresses mitophagy under non-depolarizing by positively protein import, independent ATF4 activation. Mitochondrial import regulated rate synthesis both depolarizing and stress. Without ISR, increased overwhelms machinery, reducing efficiency. Under stress, heavily impaired even with active leading significant PINK1 accumulation. contrast, allows more efficient presence resulting lower mitophagy. becomes severely compromised, causing accumulation reach threshold necessary trigger These reveal novel link between ISR-regulated synthesis, offering potential therapeutic targets diseases associated dysfunction.

Language: Английский

Citations

0