The Unfolded Protein Response of the Endoplasmic Reticulum Supports Mitochondrial Biogenesis by Buffering Nonimported Proteins

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2023 Jun 28

PMID 37379206

Authors

Katharina Knoringer

Carina Groh

Lena Kramer

Kevin C Stein

Katja G Hansen

Jannik Zimmermann

Bruce Morgan

Johannes M Herrmann

Judith Frydman

Felix Boos

Affiliations

Soon will be listed here.

Abstract

Almost all mitochondrial proteins are synthesized in the cytosol and subsequently targeted to mitochondria. The accumulation of nonimported precursor proteins occurring upon mitochondrial dysfunction can challenge cellular protein homeostasis. Here we show that blocking protein translocation into mitochondria results in the accumulation of mitochondrial membrane proteins at the endoplasmic reticulum, thereby triggering the unfolded protein response (UPR). Moreover, we find that mitochondrial membrane proteins are also routed to the ER under physiological conditions. The level of ER-resident mitochondrial precursors is enhanced by import defects as well as metabolic stimuli that increase the expression of mitochondrial proteins. Under such conditions, the UPR is crucial to maintain protein homeostasis and cellular fitness. We propose the ER serves as a physiological buffer zone for those mitochondrial precursors that cannot be immediately imported into mitochondria while engaging the UPR to adjust the ER proteostasis capacity to the extent of precursor accumulation.

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References

Bockler S, Westermann B . Mitochondrial ER contacts are crucial for mitophagy in yeast. Dev Cell. 2014; 28(4):450-8. DOI: 10.1016/j.devcel.2014.01.012. View

Tran J, Tomsic L, Brodsky J . A Cdc48p-associated factor modulates endoplasmic reticulum-associated degradation, cell stress, and ubiquitinated protein homeostasis. J Biol Chem. 2010; 286(7):5744-55. PMC: 3037687. DOI: 10.1074/jbc.M110.179259. View

Moehle E, Shen K, Dillin A . Mitochondrial proteostasis in the context of cellular and organismal health and aging. J Biol Chem. 2018; 294(14):5396-5407. PMC: 6462515. DOI: 10.1074/jbc.TM117.000893. View

Williams C, Jan C, Weissman J . Targeting and plasticity of mitochondrial proteins revealed by proximity-specific ribosome profiling. Science. 2014; 346(6210):748-51. PMC: 4263316. DOI: 10.1126/science.1257522. View

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

Chawla A, Chakrabarti S, Ghosh G, Niwa M . Attenuation of yeast UPR is essential for survival and is mediated by IRE1 kinase. J Cell Biol. 2011; 193(1):41-50. PMC: 3082189. DOI: 10.1083/jcb.201008071. View

Cabantous S, Terwilliger T, Waldo G . Protein tagging and detection with engineered self-assembling fragments of green fluorescent protein. Nat Biotechnol. 2004; 23(1):102-7. DOI: 10.1038/nbt1044. View

Martensson C, Priesnitz C, Song J, Ellenrieder L, Doan K, Boos F . Mitochondrial protein translocation-associated degradation. Nature. 2019; 569(7758):679-683. DOI: 10.1038/s41586-019-1227-y. View

Smoyer C, Katta S, Gardner J, Stoltz L, McCroskey S, Bradford W . Analysis of membrane proteins localizing to the inner nuclear envelope in living cells. J Cell Biol. 2016; 215(4):575-590. PMC: 5119940. DOI: 10.1083/jcb.201607043. View

10.

Tsaytler P, Harding H, Ron D, Bertolotti A . Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science. 2011; 332(6025):91-4. DOI: 10.1126/science.1201396. View

11.

Hetz C, Mollereau B . Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat Rev Neurosci. 2014; 15(4):233-49. DOI: 10.1038/nrn3689. View

12.

Rojo E, Guiard B, Neupert W, Stuart R . Sorting of D-lactate dehydrogenase to the inner membrane of mitochondria. Analysis of topogenic signal and energetic requirements. J Biol Chem. 1998; 273(14):8040-7. DOI: 10.1074/jbc.273.14.8040. View

13.

Shakya V, Barbeau W, Xiao T, Knutson C, Schuler M, Hughes A . A nuclear-based quality control pathway for non-imported mitochondrial proteins. Elife. 2021; 10. PMC: 7993989. DOI: 10.7554/eLife.61230. View

14.

Pedelacq J, Cabantous S, Tran T, Terwilliger T, Waldo G . Engineering and characterization of a superfolder green fluorescent protein. Nat Biotechnol. 2005; 24(1):79-88. DOI: 10.1038/nbt1172. View

15.

Hayashi T, Rizzuto R, Hajnoczky G, Su T . MAM: more than just a housekeeper. Trends Cell Biol. 2009; 19(2):81-8. PMC: 2750097. DOI: 10.1016/j.tcb.2008.12.002. View

16.

Dederer V, Khmelinskii A, Huhn A, Okreglak V, Knop M, Lemberg M . Cooperation of mitochondrial and ER factors in quality control of tail-anchored proteins. Elife. 2019; 8. PMC: 6586462. DOI: 10.7554/eLife.45506. View

17.

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z . clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2(3):100141. PMC: 8454663. DOI: 10.1016/j.xinn.2021.100141. View

18.

Costa R, Peruzzo R, Bachmann M, Monta G, Vicario M, Santinon G . Impaired Mitochondrial ATP Production Downregulates Wnt Signaling via ER Stress Induction. Cell Rep. 2019; 28(8):1949-1960.e6. DOI: 10.1016/j.celrep.2019.07.050. View

19.

Chartron J, Hunt K, Frydman J . Cotranslational signal-independent SRP preloading during membrane targeting. Nature. 2016; 536(7615):224-8. PMC: 5120976. DOI: 10.1038/nature19309. View

20.

Di Bartolomeo F, Malina C, Campbell K, Mormino M, Fuchs J, Vorontsov E . Absolute yeast mitochondrial proteome quantification reveals trade-off between biosynthesis and energy generation during diauxic shift. Proc Natl Acad Sci U S A. 2020; 117(13):7524-7535. PMC: 7132131. DOI: 10.1073/pnas.1918216117. View