Epistasis-driven identification of SLC25A51 as a regulator of human mitochondrial NAD import
Open accessAbstract
About a thousand genes in the human genome encode for membrane transporters. Among these, several solute carrier proteins (SLCs), representing the largest group of transporters, are still orphan and lack functional characterization. We reasoned that assessing genetic interactions among SLCs may be an efficient way to obtain functional information allowing their deorphanization. Here we describe a network of strong genetic interactions indicating a contribution to mitochondrial respiration and redox metabolism for SLC25A51/MCART1, an uncharacterized member of the SLC25 family of transporters. Through a combination of metabolomics, genomics and genetics approaches, we demonstrate a role for SLC25A51 as enabler of mitochondrial import of NAD, showcasing the potential of genetic interaction-driven functional gene deorphanization.
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NADH is not efficiently transported across the inner mitochondrial membrane, necessitating electron shuttle pathways that transport reducing equivalents from the cytoplasm into the mitochondrial matrix for oxidation in the ETC.
“Notably, while NAD+ itself can be imported into mitochondria through SLC25A51–MCART1 (98, 99, 100), NADH is not efficiently transported.”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [98]
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References 56 · Cited by 123
- Authors
- Girardi, E., Agrimi, G., Goldmann, U., Fiume, G., Lindinger, S., Sedlyarov, V., Srndic, I., Gürtl, B., Agerer, B., Kartnig, F., Scarcia, P., Di Noia, M. A., Liñeiro, E., Rebsamen, M., Wiedmer, T., Bergthaler, A., Palmieri, L., & Superti-Furga, G.
- Affiliations
- Austrian Academy of Sciences (AT)
- University of Bari Aldo Moro (IT)
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IT)
- ORCID
- Venue
- Nature Communications
- Published
- 2020-12-01
- Volume
- 11
- Issue
- 1
- Pages
- 6145-6145
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7708531
- OpenAlex
- W3109789346
- Cited by
- 123
- References
- 56
- Citations by year
- 2026: 11 · 2025: 18 · 2024: 25 · 2023: 29 · 2022: 20 · 2021: 20
- FWCI
- 5.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion, cc-by)
- Funders
- Österreichischen Akademie der Wissenschaften
- Austrian Science Fund (P29250, FWF P29250-B30, DK W1212, W 1212)
- H2020 European Research Council (677006, 695214)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- epistasis, genetic interactions, solute carrier proteins, mitochondrial respiration, redox metabolism, mitochondrial transporters
- MeSH terms
- Uncoupling Protein 1, Biological Transport, Epistasis, Genetic, Humans, Mitochondria, NAD, Oxidation-Reduction
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