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Protein homeostasis is maintained by proteasomes containing PSMB9 induced by EEF1A2 upon mitochondrial stress

ABSTRACT: Perturbed proteostasis and mitochondrial dysfunction are often associated with age-related diseases such as Alzheimer’s and Parkinson’s diseases. However, the link between them remains incompletely understood. Mitochondrial dysfunction causes proteostasis imbalance, and cells respond to restore proteostasis by increasing proteasome activity and molecular chaperons in yeast and C. elegans. Here, we demonstrate the presence of similar responses in humans. Mitochondrial dysfunction upregulates a small heat shock protein HSPB1 and an immunoproteasome subunit PSMB9 leading to an increase in proteasome activity. HSPB1 and PSMB9 are required to prevent protein aggregation upon mitochondrial dysfunction. Moreover, PSMB9 expression is dependent on a translation elongation factor EEF1A2, and PSMB9-containing proteasomes are located near mitochondria, enabling fast local degradation of aberrant proteins. Our findings put a step forward in understanding the stress response triggered by mitochondrial dysfunction, and may be useful for therapeutic strategies to prevent or delay the onset of age-related diseases and attenuate their progression.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: Remigiusz Serwa

LAB HEAD: Prof. Agnieszka Chacinska

PROVIDER: PXD031374 | Pride | 2023-07-03

REPOSITORIES: Pride

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			Action	DRS
	LS_3_KO1_2_5ul.raw	Raw
	LS_3_KO2_2_5ul.raw	Raw
	LS_3_KO3_2_5ul.raw	Raw
	LS_3_WT1_2_5ul.raw	Raw
	LS_3_WT2_2_5ul.raw	Raw

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Project description:Perturbed proteostasis and mitochondrial dysfunction are often associated with age-related diseases such as Alzheimer’s and Parkinson’s diseases. However, the link between them remains incompletely understood. Mitochondrial dysfunction causes proteostasis imbalance, and cells respond to restore proteostasis by increasing proteasome activity and molecular chaperons in yeast and C. elegans. Here, we demonstrate the presence of similar responses in humans. Mitochondrial dysfunction upregulates a small heat shock protein HSPB1 and an immunoproteasome subunit PSMB9 leading to an increase in proteasome activity. HSPB1 and PSMB9 are required to prevent protein aggregation upon mitochondrial dysfunction. Moreover, PSMB9 expression is dependent on a translation elongation factor EEF1A2, and PSMB9-containing proteasomes are located near mitochondria, enabling fast local degradation of aberrant proteins. Our findings put a step forward in understanding the stress response triggered by mitochondrial dysfunction, and may be useful for therapeutic strategies to prevent or delay the onset of age-related diseases and attenuate their progression.

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Protein homeostasis is maintained by proteasomes containing PSMB9 induced by EEF1A2 upon mitochondrial stress

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Mitochondrial dysfunction induces oxidative stress and an impaired ubiquitin proteasome system to trigger the pathogenesis of Frontal Fibrosing Alopecia (FFA)

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2021-11-27 | GSE188809 | GEO

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