Efficient import of nuclear-encoded proteins into mitochondria is crucial for proper mitochondrial function. The conserved translation factor eIF5A binds ribosomes, alleviating stalling at polyproline-encoding sequences. eIF5A impacts mitochondrial function across species, though the precise molecular mechanism is unclear. We found that eIF5A depletion in yeast reduces the translation and levels of the TCA cycle and oxidative phosphorylation proteins. Loss of eIF5A causes mitoprotein precursors to accumulate in the cytosol and triggers a mitochondrial import stress response. We identify an essential polyproline protein as a direct target of eIF5A: the mitochondrial inner membrane protein and translocase component Tim50. Thus, eIF5A controls mitochondrial protein import by alleviating ribosome stalling along Tim50 mRNA at the mitochondrial surface. Removal of polyprolines from Tim50 partially rescues the mitochondrial import stress response and translation of oxidative phosphorylation genes. Overall, our findings elucidate how eIF5A impacts the mitochondrial function by promoting efficient translation and reducing ribosome stalling of co-translationally imported proteins, thereby positively impacting the mitochondrial import process.
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2 December 2024
Article|
November 07 2024
eIF5A controls mitoprotein import by relieving ribosome stalling at TIM50 translocase mRNA
Marina Barba-Aliaga
,
(Conceptualization, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
Instituto de Biotecnología y Biomedicina (Biotecmed), Universitat de València
, València, Spain
2Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas,
Universitat de València
, València, Spain
3Department of Chemistry and Biochemistry,
University of California San Diego
, La Jolla, CA, USA
Marina Barba-Aliaga: [email protected]
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Vanessa Bernal
,
Vanessa Bernal
(Formal analysis, Investigation, Visualization)
1
Instituto de Biotecnología y Biomedicina (Biotecmed), Universitat de València
, València, Spain
2Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas,
Universitat de València
, València, Spain
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Cynthia Rong
,
Cynthia Rong
(Investigation, Methodology)
3Department of Chemistry and Biochemistry,
University of California San Diego
, La Jolla, CA, USA
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Madeleine E. Volfbeyn
,
Madeleine E. Volfbeyn
(Investigation, Validation)
3Department of Chemistry and Biochemistry,
University of California San Diego
, La Jolla, CA, USA
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Keguang Zhang
,
Keguang Zhang
(Investigation)
3Department of Chemistry and Biochemistry,
University of California San Diego
, La Jolla, CA, USA
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Brian M. Zid
,
(Conceptualization, Formal analysis, Funding acquisition, Investigation, Project administration, Supervision, Writing - original draft, Writing - review & editing)
3Department of Chemistry and Biochemistry,
University of California San Diego
, La Jolla, CA, USA
Brian M. Zid: [email protected]
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Paula Alepuz
(Conceptualization, Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing)
1
Instituto de Biotecnología y Biomedicina (Biotecmed), Universitat de València
, València, Spain
2Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas,
Universitat de València
, València, Spain
Correspondence to Paula Alepuz: [email protected]
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Marina Barba-Aliaga
Conceptualization, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Instituto de Biotecnología y Biomedicina (Biotecmed), Universitat de València
, València, Spain
2Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas,
Universitat de València
, València, Spain
3Department of Chemistry and Biochemistry,
University of California San Diego
, La Jolla, CA, USA
Vanessa Bernal
Formal analysis, Investigation, Visualization
1
Instituto de Biotecnología y Biomedicina (Biotecmed), Universitat de València
, València, Spain
2Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas,
Universitat de València
, València, Spain
Cynthia Rong
Investigation, Methodology
3Department of Chemistry and Biochemistry,
University of California San Diego
, La Jolla, CA, USA
Madeleine E. Volfbeyn
Investigation, Validation
3Department of Chemistry and Biochemistry,
University of California San Diego
, La Jolla, CA, USA
Keguang Zhang
Investigation
3Department of Chemistry and Biochemistry,
University of California San Diego
, La Jolla, CA, USA
Brian M. Zid
Conceptualization, Formal analysis, Funding acquisition, Investigation, Project administration, Supervision, Writing - original draft, Writing - review & editing
3Department of Chemistry and Biochemistry,
University of California San Diego
, La Jolla, CA, USA
Paula Alepuz
Conceptualization, Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing
1
Instituto de Biotecnología y Biomedicina (Biotecmed), Universitat de València
, València, Spain
2Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas,
Universitat de València
, València, Spain
Correspondence to Paula Alepuz: [email protected]
Marina Barba-Aliaga: [email protected]
Brian M. Zid: [email protected]
Disclosures: The authors declare no competing interests exist.
Received:
April 18 2024
Revision Received:
July 29 2024
Accepted:
September 19 2024
Online ISSN: 1540-8140
Print ISSN: 0021-9525
Funder(s):
Agencia Estatal de Investigación
- Award Id(s): PID2020-120066RB-I00,PID2023-152214NB-I00,FPU2017/03542
Funder(s):
Ministry of Science, Innovation and Universities
Funder(s):
National Institutes of Health
- Award Id(s): R35GM128798
Funder(s):
Generalitat Valenciana
- Award Id(s): AICO/2020/086,CIAICO/2022/237
Funder(s):
European Social Fund
© 2024 Barba-Aliaga et al.
2024
Barba-Aliaga et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2024) 223 (12): e202404094.
Article history
Received:
April 18 2024
Revision Received:
July 29 2024
Accepted:
September 19 2024
Citation
Marina Barba-Aliaga, Vanessa Bernal, Cynthia Rong, Madeleine E. Volfbeyn, Keguang Zhang, Brian M. Zid, Paula Alepuz; eIF5A controls mitoprotein import by relieving ribosome stalling at TIM50 translocase mRNA. J Cell Biol 2 December 2024; 223 (12): e202404094. doi: https://doi.org/10.1083/jcb.202404094
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