MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion
Abstract
The mitochondrial (mt) DNA depletion syndromes (MDDS) are genetic disorders characterized by a severe, tissue-specific decrease of mtDNA copy number, leading to organ failure. There are two main clinical presentations: myopathic (OMIM 609560) and hepatocerebral (OMIM 251880). Known mutant genes, including TK2, SUCLA2, DGUOK and POLG, account for only a fraction of MDDS cases. We found a new locus for hepatocerebral MDDS on chromosome 2p21-23 and prioritized the genes on this locus using a new integrative genomics strategy. One of the top-scoring candidates was the human ortholog of the mouse kidney disease gene Mpv17. We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product, MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes oxidative phosphorylation (OXPHOS) failure and mtDNA depletion, not only in affected individuals but also in Mpv17-/- mice.
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The mouse liver shows a large decrease in mtDNA content, with only 4% of WT; kidney is less affected with 60% of WT, and glomerular podocytes are severely affected while renal tubules are relatively normal.
“Interestingly, the liver in the mouse shows the expected large decrease in mtDNA content, with only 4% of the content compared to WT. In contrast, the kidney is less affected in this regard, with overall 60% of the levels seen in WT, but even within this tissue the effect is heterogeneous, with the glomerular podocytes severely affected while the renal tubules were relatively normal(Spinazzola et”
From A defect in the mitochondrial protein Mpv17 underlies the transparent casper zebrafish (2017) · cites this paper as Spinazzola et al., 2006
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- Authors
- Spinazzola, A., Viscomi, C., Fernandez-Vizarra, E., Carrara, F., D'Adamo, P., Calvo, S., Marsano, R. M., Donnini, C., Weiher, H., Strisciuglio, P., Parini, R., Sarzi, E., Chan, A., DiMauro, S., Rötig, A., Gasparini, P., Ferrero, I., Mootha, V. K., Tiranti, V., & Zeviani, M.
- Affiliations
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Broad Institute (US)
- University of Parma (IT)
- Hochschule Bonn-Rhein-Sieg (DE)
- Magna Graecia University (IT)
- Hôpital Necker-Enfants Malades (FR)
- University of Alberta (CA)
- Columbia University (US)
- University of Trieste (IT)
- Corresponding author
- Zeviani, Massimo
- ORCID
- Venue
- Nature Genetics
- Published
- 2006-04-02
- Volume
- 38
- Issue
- 5
- Pages
- 570-575
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2166483810
- Cited by
- 427
- References
- 1
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 12 · 2023: 9 · 2022: 13 · 2021: 15 · 2020: 16 · 2019: 16 · 2018: 17 · 2017: 12 · 2016: 14 · 2015: 19 · 2014: 24 · 2013: 32 · 2012: 29
- FWCI
- 15.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
- Publication Server of Bonn-Rhein-Sieg University of Applied Sciences (Bonn-Rhein-Sieg University of Applied Sciences) (submittedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- European Commission
- Fondazione Telethon
- Fondazione Pierfranco e Luisa Mariani
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- MPV17, mitochondrial DNA depletion syndrome, mitochondrial inner membrane proteins, mitochondrial DNA copy number, peroxisome biogenesis, integrative genomics
- MeSH terms
- Amino Acid Sequence, Animals, Cells, Cultured, Chromosomes, Human, Pair 2, Cloning, Molecular, DNA, Mitochondrial, Female, Fluorescent Antibody Technique, Humans, Intracellular Membranes, Liver Diseases, Male, Membrane Proteins, Mitochondria, Molecular Sequence Data, Mutation, Pedigree, Syndrome, Mice
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