bims-cesemi 2026-05-03 papers

Issue of 2026–05–03
six papers selected by
Julio Cesar Cardenas, Universidad Mayor

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

Cold Spring Harb Perspect Biol. 2026 Apr 27. pii: a041771. [Epub ahead of print]

Pharmacological and Biological Tools to Inhibit IP3 Receptors.

Robbe Van Gorp, Tihomir Tomašič, Jan B Parys, Martin D Bootman, Geert Bultynck.

Inositol 1,4,5-trisphosphate receptors (IP3Rs) are an important class of ion channels that mediate calcium (Ca2+) release from the endoplasmic reticulum and other organelles, thereby critically controlling cell function. Dysregulation of these channels, including excessive IP3R activity, has been implicated in a plethora of diseases. The current arsenal of tools to acutely inhibit IP3Rs consists of various antagonists with distinct mechanisms of action. Yet, most suffer from limited selectivity due to their impact on several other Ca2+-transport systems, cellular targets, and/or lack of membrane permeability. This shortage of highly specific IP3R antagonists limits biomedical research and hampers the development of therapeutic strategies targeting IP3R channels. This work aims to provide a comprehensive overview of IP3R-antagonizing tools that were developed and characterized over the past decades, focusing on three classes of molecules: (1) pharmacological antagonists that directly affect IP3Rs by binding to the channel, (2) biological antagonists that directly affect IP3Rs by interacting with the IP3R, and (3) antagonism of IP3R activity via regulation of the phosphoinositide signaling pathway upstream of IP3Rs.

DOI: https://doi.org/10.1101/cshperspect.a041771

Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2609146123

Exercise works-if mitochondria do.

Jianing Xu.

DOI: https://doi.org/10.1073/pnas.2609146123

Nature. 2026 May 01.

Briefing Chat: Stressed mitochondria spawn new 'organelles' in cells.

Benjamin Thompson, Shamini Bundell.

Keywords: Cell biology; Evolution; Palaeontology; Zoology

DOI: https://doi.org/10.1038/d41586-026-01439-2

Eur J Pharmacol. 2026 Apr 24. pii: S0014-2999(26)00375-4. [Epub ahead of print]1024 178893

Mitochondrial dysfunction and senescence accompany glioblastoma cell death triggered by a putative metabolic inhibitor.

Anjali Yadav, Shraddha Bhutkar, Shrikant Barot, Ajinkya A Aher, Kinjal Patel, Aaron Muth, Vikas Dukhande.

Glioblastoma (GBM) is a fatal cancer with a dismal prognosis and a dire need for novel chemotherapeutics. Metabolic reprogramming is an established hallmark of cancer. In our previous study on GBM, we aimed at targeting the metabolic reprogramming of cancer by using stiripentol (STP), a putative lactate dehydrogenase (LDH) inhibitor and an FDA-approved anti-epileptic drug. However, the precise mechanism of STP's anti-cancer activity remains unclear. We aimed to elucidate the mechanism of action of STP in GBM to further develop STP as a therapeutic. We employed a multiomic approach followed by metabolic and cellular assays. STP treatment induced genetic and metabolic alterations in GBM cells. Inhibition of LDH by STP was moderate but not potent. The cellular changes were accompanied by an increase in reactive oxygen species, a decrease in mitochondrial membrane potential, and induction of senescence in GBM cells. Our research indicates that further research in senescence-inducing agents and novel LDH inhibitors can provide novel therapeutics for GBM.

Keywords: Glioblastoma; Mitochondrial dysfunction; Multiomic; Reactive oxygen species; Seahorse; Senescence; Stiripentol

DOI: https://doi.org/10.1016/j.ejphar.2026.178893