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Beyond the known role of the tubular ER protein RTN4, the factors regulating this process are poorly defined. Here, we show that repressing the ER protein ERLIN2 in human fibroblasts depletes ER\u2013mitochondrial contact sites and inhibits mitochondrial DNA replication, as does silencing RTN4 or the ER\u2013mitochondrial tether GRP75. GRP75 or RTN4 scarcity also decreases the level of the mitochondrial calcium uniporter (MCU), whose inhibition blocks mitochondrial DNA synthesis. Because ERMCS depletion did not diminish mitochondrial calcium, and MCU complex can transport manganese, we tested whether manganese could bypass these defects. Manganese supplementation restored mitochondrial DNA replication in cells lacking ERMCS or with inhibited MCU, identifying manganese as a critical mediator. We then considered mitochondrial transcription as a potential manganese target, since it provides both transcripts for gene expression and primers for DNA replication.\u00a0In vitro, manganese inhibits transcription re-start and stimulates RNA synthesis at the light-strand origin of replication. These findings support a model in which ER\u2013mitochondrial contact sites, in conjunction with MCU, deliver manganese from the ER to mitochondria to promote DNA replication, potentially by modulating mitochondrial RNA polymerase activity.<\/jats:p>","DOI":"10.1093\/nar\/gkag233","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T12:40:15Z","timestamp":1772800815000},"source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial DNA replication is regulated by endoplasmic reticulum-mitochondrial contact sites, the mitochondrial calcium uniporter, and manganese"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0593-1675","authenticated-orcid":false,"given":"Amaia","family":"Lopez\u00a0de\u00a0Arbina","sequence":"first","affiliation":[{"name":"Biogipuzkoa Health Research Institute , San Sebasti\u00e1n 20014 ,","place":["Spain"]},{"name":"CIBERNED (Center for Networked Biomedical Research on Neurodegenerative 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Basque Foundation for Science , Bilbao 48013 ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8850-7794","authenticated-orcid":false,"given":"Nerea","family":"Osinalde","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, EHU, 01006 Vitoria\u2013Gasteiz and 48940 Leioa ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2409-8263","authenticated-orcid":false,"given":"Ainara","family":"Vallejo-Illaramendi","sequence":"additional","affiliation":[{"name":"Biogipuzkoa Health Research Institute , San Sebasti\u00e1n 20014 ,","place":["Spain"]},{"name":"CIBERNED (Center for Networked Biomedical Research on Neurodegenerative Diseases), Ministry of Economy and Competitiveness, Institute Carlos III , Madrid 28031 ,","place":["Spain"]},{"name":"Department of Pediatrics, University of the Basque Country (EHU), 20014, 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