Biology subjects

Argenton, F.

Publications and source records attributed to Argenton, F..

4 recordsLinked to original sources

bioRxiv2026

Endothelial RRM2B-dependent mitochondrial DNA signalling drives doxorubicin-cardiotoxicity

Doxorubicin remains a mainstay of cancer therapy, yet its clinical use is constrained by severe cardiotoxicity, classically attributed to cardiomyocyte death. Here, we identify endothelial inflammation driven by mitochondrial DNA (mtDNA) turnover and release as a critical mediator of doxorubicin-induced cardiac injury. In vivo, a standard doxorubicin regimen activates the cGAS-STING innate immune pathway in endothelial cells before cardiomyocyte dysfunction or death occurs. Mechanistically, doxorubicin recruits the stress-inducible ribonucleotide reductase subunit RRM2B (p53R2) that normally sustains the mitochondrial deoxyribonucleotide pool, to promote aberrant mtDNA turnover and release, fuelling sterile inflammation. The FDA-approved BAX inhibitor Eltrombopag suppresses mtDNA release, attenuates endothelial inflammation, and prevents doxorubicin cardiotoxicity in vivo without compromising anticancer efficacy. These findings reveal an unrecognized proinflammatory role of RRM2B and establish endothelial inflammation as a central driver of chemotherapy-related cardiac injury, identifying the cardiac endothelium as a tractable target for cardioprotection during cancer treatment.

cell biology↗

bioRxiv2021

STAT3 and HIF1α cooperatively mediate the transcriptional and physiological responses to hypoxia

STAT3 and HIF1 are two fundamental transcription factors involved in many merging processes, like angiogenesis, metabolism, and cell differentiation. Notably, under pathological conditions, the two factors have been shown to interact genetically, but both the molecular mechanisms underlying such interactions and their relevance under physiological conditions remain unclear. Here we report that STAT3 is required for the HIF1-dependent response to hypoxia. In Stat3 knock-out pluripotent embryonic stem cells (ESCs), a large fraction of HIF1 target genes is not induced by hypoxia. Mechanistically, STAT3 does not regulate neither HIF1 expression nor stability, rather, it physically interacts with it in the nucleus. In vivo, we observed that both genetic and chemical inactivation of Stat3 blunted physiological responses to hypoxia, such as angiogenesis, erythropoiesis, and immune cell mobilization. Such defects were accompanied with faulty transcriptional activity of HIF1. In sum, our data reveal that STAT3 and HIF1 cooperatively mediate the physiological response to hypoxia.

developmental biology↗

bioRxiv2020

HIF1a-dependent induction of the mitochondrial chaperone TRAP1 regulates bioenergetic adaptations to hypoxia

The mitochondrial paralog of the Hsp90 chaperone family TRAP1 is often induced in tumors, but the mechanisms controlling its expression, as well as its physiological functions remain poorly understood. Here, we find that TRAP1 is highly expressed in the early stages of Zebrafish development, and its ablation delays embryogenesis while increasing mitochondrial respiration of fish larvae. TRAP1 expression is enhanced by hypoxic conditions both in developing embryos and in cancer models of Zebrafish and mammals. The TRAP1 promoter contains evolutionary conserved hypoxic responsive elements, and HIF1 stabilization increases TRAP1 levels. TRAP1 inhibition by selective compounds or by genetic knock-out maintains a high level of respiration in Zebrafish embryos after exposure to hypoxia. Our data identify TRAP1 as a primary regulator of mitochondrial bioenergetics in highly proliferating cells following reductions in oxygen tension and HIF1 stabilization.

biochemistry↗

bioRxiv2020

Mitochondrial STAT3 regulates proliferation of tissue stem cells.

The STAT3 transcription factor, acting both in the nucleus and mitochondria, maintains embryonic stem cell pluripotency and promotes their proliferation. In this work, using zebrafish, we determined in vivo that mitochondrial STAT3 regulates mtDNA transcription in embryonic and larval stem cell niches and that this activity affects their proliferation rates. As a result, we demonstrated that STAT3 import inside mitochondria requires Y705 phosphorylation by Jak2, while its mitochondrial transcriptional activity, as well as its effect on proliferation, depends on the MAPK target S727. These data were confirmed using mouse embryonic stem cells: Y705 mutated STAT3 cannot enter the mitochondrion while the S727 mutation does not affect mitochondrial import of the protein. Surprisingly, STAT3-dependent increase of mitochondrial transcription seems independent from STAT3 binding to STAT3 responsive elements. Finally, loss of function experiments, with chemical inhibition of JAK/STAT3 pathway or genetic ablation of stat3 gene, demonstrated that STAT3 is also required for cell proliferation in the intestine of zebrafish.

developmental biology↗