Optimized Mitochondrial Targeting of Proteins Encoded by Modified mRNAs Rescues Cells Harboring Mutations in mtATP6
Open accessAbstract
Mitochondrial disease may be caused by mutations in the protein-coding genes of the mitochondrial genome. A promising strategy for treating such diseases is allotopic expression-the translation of wild-type copies of these proteins in the cytosol, with subsequent translocation into the mitochondria, resulting in rescue of mitochondrial function. In this paper, we develop an automated, quantitative, and unbiased screening platform to evaluate protein localization and mitochondrial morphology. This platform was used to compare 31 mitochondrial targeting sequences and 15 3' UTRs in their ability to localize up to 9 allotopically expressed proteins to the mitochondria and their subsequent impact on mitochondrial morphology. Taking these two factors together, we synthesized chemically modified mRNAs that encode for an optimized allotopic expression construct for mtATP6. These mRNAs were able to functionally rescue a cell line harboring the 8993T > G point mutation in the mtATP6 gene.
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Allotropic expression of wild-type mtDNA-encoded genes can salvage mitochondrial functionality via mitochondrial targeting sequences and 3'UTRs.
“In the context of allotropic expression, the genes encoded by wild-type mtDNA are transcribed within the nucleus. Consequently, resulting non-coding RNAs (ncRNAs) or proteins can be transported into the mitochondria, thereby salvaging mitochondrial functionality. This transportation is facilitated by mitochondrial targeting sequences (MTSs) and 3′ untranslated regions (3′UTRs)”
From The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer’s disease (2024) · cites this paper as Chin et al, 2018
The Summary reports that allotopically expressed wild-type mtATP6 protein can be targeted to mitochondria and functionally rescue cells with an mtATP6 mutation. The Results identify mitochondrial targeting sequences as a means of importing proteins, but the Discussion says none of the tested 3′ UTRs significantly improved mitochondrial colocalization. The cited paper therefore does not establish the sentence’s implication that both MTSs and 3′ UTRs facilitated the rescue; the supplied passages also do not support transport of non-coding RNAs. (LLM, conf=0.88)
Experimental — accuracy not yet measuredFusion of lncMtDloop with the 3′UTR of MRPS12 facilitates its targeted localization to the mitochondrial surface.
“Our optimization process involved the fusion of lncMtDloop with the 3′UTR of MRPS12, facilitating its targeted localization to the mitochondrial surface—a technique supported by previous research (Chin et al, 2018; Wang et al, 2012b).”
From The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer’s disease (2024) · cites this paper as Chin et al, 2018
The Results state that specific 3′ UTRs have been used to direct mRNAs to the mitochondrial surface. Our copy does not identify the MRPS12 3′ UTR or test its fusion with lncMtDloop, so it supports the general rationale but not the specific construct or its claimed localization. (LLM, conf=0.82)
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“In addition, as the use of natural MTS is extremely limited due to a significant lack of MTS inter-compatibility [ 18 , 19 ], there is a need for enhanced strategies to optimize mitochondrial allotopic proteins uptake through engineered MTS.”
Gene Therapy Tools for Diseases Caused by Mutations of the Mitochondrial Genome
Simonov, V., & Rastorguev, S. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27125517 · Cited by 1 · see citing works
“However, a subsequent study by Chin et al., which evaluated 31 MTS and 15 3 ′ UTRs for their ability to localize allotopically expressed proteins, concluded that the choice of MTS is the primary determinant of successful optimization, while 3 ′ UTR optimization exerts negligible influence [48].”
Optimized ND4 allotopic expression for gene therapy of Leber’s hereditary optic neuropathy
Lapshin, E., Egorov, A., Malogolovkin, A., Gasanov, N., Smirnikhina, S., Tabakov, V., & Karabelsky, A. (2026) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2026.1765995
“The optimal charge, length, and structure of the MTS depend on the sequence and structure of the transported protein itself (Chin et al., 2018).”
Gombeau, K., Wan, R., James, J. S., Tribouillard-Tanvier, D., & Cai, Y.-Z. (2026) · bioRxiv · doi:10.64898/2026.02.22.707306
“This is in line with previously reported results (8).”
Lear, S. K., Nuñez, J., & Shipman, S. L. (2023) · bioRxiv · doi:10.1101/2023.04.03.535288
- Authors
- Chin, R. M., Panavas, T., Brown, J. M., & Johnson, K. K.
- Affiliations
- Alexion Pharmaceuticals (United States) (US)
- Boehringer Ingelheim (United States) (US)
- Wave Life Sciences (United States) (US)
- Corresponding author
- Chin, Randall Marcelo
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 22
- Issue
- 11
- Pages
- 2818-2826
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2790643520
- Cited by
- 50
- References
- 44
- Citations by year
- 2026: 11 · 2025: 6 · 2024: 7 · 2023: 10 · 2022: 3 · 2021: 4 · 2020: 1 · 2019: 5 · 2018: 3
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Alexion Pharmaceuticals
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- mitochondrial targeting, allotopic expression, mitochondrial disease, chemically modified mRNA, mitochondrial targeting sequence, 3' untranslated region, mitochondrial morphology, protein localization, mitochondrial DNA mutations
- MeSH terms
- Humans, Mutation, RNA, Messenger, Transfection, Mitochondrial Proteins
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