bims-mitran 2026-05-03 papers

Issue of 2026–05–03
two papers selected by
Andreas Kohler, Umeå University

Nucleic Acids Res. 2026 Apr 23. pii: gkag233. [Epub ahead of print]54(8):

Mitochondrial DNA replication is regulated by endoplasmic reticulum-mitochondrial contact sites, the mitochondrial calcium uniporter, and manganese.

Amaia Lopez de Arbina, Angelica Zamudio-Ochoa, Mikel Muñoz-Oreja, Diego Perez-Rodriguez, Laura Mosqueira-Martín, Rebecca Lasalandra, Marina Villar-Fernandez, Uxoa Fernandez-Pelayo, Laura Rodriguez-Gomez, Seungtae Lee, Francisco Gil-Bea, Nerea Osinalde, Ainara Vallejo-Illaramendi, Dmitry Temiakov, Antonella Spinazzola, Ian J Holt.

Mitochondrial DNA replication occurs at contact sites between the endoplasmic reticulum (ER) and mitochondria (ERMCS). 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-mitochondrial contact sites and inhibits mitochondrial DNA replication, as does silencing RTN4 or the ER-mitochondrial 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. In 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-mitochondrial contact sites, in conjunction with MCU, deliver manganese from the ER to mitochondria to promote DNA replication, potentially by modulating mitochondrial RNA polymerase activity.

DOI: https://doi.org/10.1093/nar/gkag233

Commun Biol. 2026 Apr 30.

Mitochondrial protein Mrpl13 regulates zebrafish liver development through the mTORC1-mitochondrial homeostasis pathway.

Xinkai Cheng, Lei Li, Shibo Fang, Lindong Yu, Chenglin Liu, Yaqi Jiao, Yang Fang, Libaijia Lin, Long Zhao, Ying Su.

The liver is the largest metabolic organ in the human body, performing functions as metabolism, secretion, immunity, and detoxification. Due to the high energy demand, liver cells are rich in mitochondria. Mitochondrial homeostasis is crucial for liver development and function, yet the molecular pathways linking mitochondrial dysfunction to liver defects remain incompletely understood. In this study, using the zebrafish model, we show that loss of Mrpl13, a component of the mitochondrial ribosomal subunit, results in pronounced abnormalities in liver development. The deficiency of Mrpl13 disrupts mitochondrial homeostasis, as evidenced by fragmentated mitochondria, impaired energy metabolism, excessive reactive oxygen species, and lipid accumulation in liver cells. Notably, loss of Mrpl13 triggers mTORC1 signaling, and treatment with the mTORC1 inhibitor rapamycin significantly alleviates liver developmental defects, suggesting that mTORC1 signaling mediates the role of Mrpl13 in regulating mitochondrial homeostasis and liver development. Overall, our findings reveal a regulatory axis involving Mrpl13, mTORC1, and mitochondrial homeostasis during liver development, providing a theoretical basis for exploring therapeutic strategies for liver defects associated with mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s42003-026-10137-8