• Alternative start codon select...

Treffer: Alternative start codon selection shapes mitochondrial function and rare human diseases.

Title:
Alternative start codon selection shapes mitochondrial function and rare human diseases.
Authors:
Ly J; Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: jimmy1996ly@gmail.com., Di Bernardo M; Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Tao YF; Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Khalizeva E; Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Giuliano CJ; Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Lourido S; Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Fleming MD; Department of Pathology, Boston Children's Hospital, Boston, MA, USA., Cheeseman IM; Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: icheese@wi.mit.edu.
Source:
Molecular cell [Mol Cell] 2025 Nov 20; Vol. 85 (22), pp. 4198-4214.e11. Date of Electronic Publication: 2025 Nov 07.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Cell Press Country of Publication: United States NLM ID: 9802571 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4164 (Electronic) Linking ISSN: 10972765 NLM ISO Abbreviation: Mol Cell Subsets: MEDLINE
Imprint Name(s):
Publication: Cambridge Ma : Cell Press
Original Publication: Cambridge, Mass. : Cell Press, c1997-
MeSH Terms:
Mitochondria*/genetics , Mitochondria*/metabolism , Mitochondria*/pathology , Rare Diseases*/genetics , Rare Diseases*/metabolism , Rare Diseases*/pathology , Codon, Initiator*/genetics , Mitochondrial Proteins*/genetics , Mitochondrial Proteins*/metabolism, Humans ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Evolution, Molecular ; Frameshift Mutation ; Alleles ; Animals ; Codon, Nonsense
Comments:
Update of: bioRxiv. 2025 Mar 27:2025.03.27.645657. doi: 10.1101/2025.03.27.645657.. (PMID: 40196624)
References:
Nucleic Acids Res. 2020 Mar 18;48(5):2312-2331. (PMID: 32020195)
Nat Rev Genet. 2004 Feb;5(2):123-35. (PMID: 14735123)
Genet Med. 2015 May;17(5):405-24. (PMID: 25741868)
PLoS Pathog. 2007 Aug 31;3(8):e115. (PMID: 17784785)
Life Sci Alliance. 2019 Sep 30;2(5):. (PMID: 31570514)
Proc Natl Acad Sci U S A. 2017 Sep 12;114(37):E7679-E7687. (PMID: 28847952)
Nat Rev Mol Cell Biol. 2010 Sep;11(9):655-67. (PMID: 20729931)
Front Microbiol. 2020 Feb 13;11:197. (PMID: 32117186)
BMC Bioinformatics. 2011 Aug 03;12:317. (PMID: 21812952)
Stem Cells. 2014 May;32(5):1230-8. (PMID: 24497442)
Nucleic Acids Res. 1987 Oct 26;15(20):8125-48. (PMID: 3313277)
Cell. 2022 Jul 7;185(14):2559-2575.e28. (PMID: 35688146)
Cell. 2022 Nov 23;185(24):4474-4487.e17. (PMID: 36334590)
Algorithms Mol Biol. 2011 Nov 24;6:26. (PMID: 22115189)
Trends Cell Biol. 2022 Mar;32(3):243-258. (PMID: 34844857)
Blood. 2013 Jul 4;122(1):112-23. (PMID: 23553769)
Front Pediatr. 2023 Mar 02;11:1001222. (PMID: 36937953)
Elife. 2022 Nov 10;11:. (PMID: 36355038)
Genes Dev. 2023 Jun 1;37(11-12):474-489. (PMID: 37433636)
Clin Chim Acta. 2021 Oct;521:244-250. (PMID: 34310935)
Nucleic Acids Res. 2013 Feb 1;41(4):2354-69. (PMID: 23275553)
Elife. 2018 Sep 11;7:. (PMID: 30204084)
J Biol Chem. 1994 May 6;269(18):13361-6. (PMID: 8175766)
Nucleic Acids Res. 2021 Jan 8;49(D1):D1541-D1547. (PMID: 33174596)
Genome Biol. 2025 Jan 21;26(1):13. (PMID: 39838450)
Cell. 2011 Nov 11;147(4):789-802. (PMID: 22056041)
Life Sci Alliance. 2024 May 21;7(7):. (PMID: 38803235)
Mol Aspects Med. 2020 Feb;71:100842. (PMID: 32029308)
Nature. 2023 May;617(7959):154-161. (PMID: 37100900)
Trends Biochem Sci. 1999 Jan;24(1):34-6. (PMID: 10087920)
J Cell Biol. 2016 May 9;213(3):315-28. (PMID: 27138257)
Cold Spring Harb Perspect Biol. 2012 Sep 01;4(9):a011403. (PMID: 22952398)
J Biol Chem. 2001 Oct 26;276(43):40041-9. (PMID: 11504732)
Cell. 2020 Apr 2;181(1):168-188. (PMID: 32220313)
Mol Phylogenet Evol. 2003 Dec;29(3):380-95. (PMID: 14615181)
Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10924-9. (PMID: 16040811)
Front Physiol. 2013 Jul 30;4:183. (PMID: 23908630)
Proc Natl Acad Sci U S A. 1990 Nov;87(21):8301-5. (PMID: 2236042)
Science. 2023 Sep 22;381(6664):eadg7492. (PMID: 37733863)
Genome Biol. 2022 May 9;23(1):111. (PMID: 35534899)
Science. 2020 Mar 6;367(6482):1140-1146. (PMID: 32139545)
Nat Biotechnol. 2019 Apr;37(4):420-423. (PMID: 30778233)
Cell. 2018 Feb 22;172(5):910-923.e16. (PMID: 29474919)
Genome Res. 2020 Jul;30(7):974-984. (PMID: 32669370)
EMBO Rep. 2021 Apr 7;22(4):e51635. (PMID: 33586863)
Traffic. 2016 Jul;17(7):720-32. (PMID: 27037871)
PLoS One. 2011 Apr 29;6(4):e19152. (PMID: 21559454)
Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):E2424-32. (PMID: 22927429)
Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10608-13. (PMID: 11526219)
Cell Syst. 2024 Apr 17;15(4):388-408.e4. (PMID: 38636458)
Nucleic Acids Res. 2025 Jan 6;53(D1):D543-D553. (PMID: 39494541)
Mol Cell. 2000 Apr;5(4):597-605. (PMID: 10882096)
Mol Cell Proteomics. 2014 May;13(5):1245-61. (PMID: 24623590)
Sci STKE. 2005 Jan 11;2005(266):pl1. (PMID: 15644491)
Front Physiol. 2015 Sep 24;6:259. (PMID: 26441678)
Biomedicines. 2022 Aug 02;10(8):. (PMID: 36009412)
Nature. 2023 Sep;621(7978):423-430. (PMID: 37674078)
Eur J Hum Genet. 2020 Feb;28(2):165-173. (PMID: 31527858)
Nature. 2024 Nov;635(8038):490-498. (PMID: 39443796)
J Biol Chem. 2004 Oct 8;279(41):42363-8. (PMID: 15280394)
Nat Cell Biol. 2025 Feb;27(2):188-201. (PMID: 39843636)
Cell Rep. 2025 Sep 23;44(9):116275. (PMID: 40946309)
J Biol Chem. 2004 Apr 2;279(14):13778-85. (PMID: 14734560)
Am J Hum Genet. 2016 Oct 6;99(4):894-902. (PMID: 27616477)
Gene. 2002 Oct 16;299(1-2):1-34. (PMID: 12459250)
Cell Syst. 2020 Aug 26;11(2):145-160.e5. (PMID: 32710835)
Nucleic Acids Res. 2024 Jul 5;52(W1):W215-W220. (PMID: 38587188)
Mol Cell. 2024 Oct 17;84(20):3967-3978.e8. (PMID: 39317199)
Nat Methods. 2012 Jul;9(7):671-5. (PMID: 22930834)
Genome Biol Evol. 2021 May 7;13(5):. (PMID: 33739376)
FEBS Lett. 2008 Apr 16;582(9):1293-7. (PMID: 18358843)
Bioinformatics. 2010 Mar 15;26(6):841-2. (PMID: 20110278)
Nucleic Acids Res. 2009 Oct;37(18):6092-104. (PMID: 19700772)
Biol Cell. 2003 May-Jun;95(3-4):169-78. (PMID: 12867081)
Genome Res. 2010 Jan;20(1):110-21. (PMID: 19858363)
Nat Microbiol. 2022 Jun;7(6):868-881. (PMID: 35484233)
Bioinformatics. 2017 Nov 01;33(21):3387-3395. (PMID: 29036616)
Semin Cell Dev Biol. 2024 Feb 15;154(Pt B):114-122. (PMID: 36925447)
Nucleic Acids Res. 2018 Jan 4;46(D1):D1062-D1067. (PMID: 29165669)
Nucleic Acids Res. 2024 Jul 8;52(12):6928-6944. (PMID: 38783074)
Blood. 2014 Oct 30;124(18):2867-71. (PMID: 25193871)
Grant Information:
R01 AI144369 United States AI NIAID NIH HHS; R01 AI158501 United States AI NIAID NIH HHS; R35 GM126930 United States GM NIGMS NIH HHS; R24 DK094746 United States DK NIDDK NIH HHS; R01 DK087992 United States DK NIDDK NIH HHS
Contributed Indexing:
Keywords: TRNT1; alternative N-terminal isoforms; alternative translation; mitochondria; proteomic diversity; rare diseases; start codon selection; translation initiation
Substance Nomenclature:
0 (Codon, Initiator)
0 (Protein Isoforms)
0 (Mitochondrial Proteins)
0 (Codon, Nonsense)
Entry Date(s):
Date Created: 20251108 Date Completed: 20251121 Latest Revision: 20251222
Update Code:
20251222
PubMed Central ID:
PMC12718117
DOI:
10.1016/j.molcel.2025.10.013
PMID:
41205602
Database:
MEDLINE

Weitere Informationen

Rare genetic diseases collectively affect millions of individuals. A common target of many rare diseases is the mitochondria, intracellular organelles that originated through endosymbiosis. Eukaryotic cells require related proteins to function both within the mitochondria and in the host cell. By analyzing N-terminal protein isoforms generated through alternative start codon selection, we identify hundreds of differentially localized isoform pairs, including dual-localized isoforms that are essential for both mitochondrial and host cell function. Subsets of dual mitochondria-localized isoforms emerged during early eukaryotic evolution, coinciding with mitochondrial endosymbiosis. Importantly, we identify dozens of rare disease alleles that affect these alternative protein variants with unique molecular and clinical consequences. Alternative start codon selection can bypass pathogenic nonsense and frameshift mutations, thereby selectively eliminating specific isoforms, which we term isoform-selective alleles (ISAs). Together, our findings illuminate the evolutionary and pathological relevance of alternative translation, offering insights into the molecular basis of rare human diseases.
(Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

Declaration of interests The authors declare no competing interests.