Biology subjects

Aranda, J. F.

Publications and source records attributed to Aranda, J. F..

2 recordsLinked to original sources

bioRxiv2026

MT4-MMP/NRP1 axis is required for balanced angiogenesis in the embryonic brain

Angiogenesis is essential for embryonic brain development and tissue repair, yet the mechanisms that spatiotemporally coordinate endothelial behavior to ensure balanced vascular remodeling remain elusive. Here, we identify the glycosylphosphatidylinositol (GPI)-anchored protease MT4-MMP as a critical, context-dependent determinant of angiogenic growth. Global loss of MT4-MMP transiently impairs vascular network formation in the embryonic hindbrain, whereas endothelial-specific deletion triggers an aberrant angiogenesis characterized by increased vessel density, branching, and a profound loss of vascular organization. This dual phenotype reveals MT4-MMP as a fundamental coordinator of neurovascular development. Consistently, MT4-MMP expression was dynamically regulated during wound repair, and its absence amplifies angiogenesis and accelerates wound closure in adult skin, highlighting its role in maintaining vascular homeostasis postnatally. Mechanistically, MT4-MMP-deficient endothelial cells exhibit impaired polarization and sustained, rather than transient, VEGFA-induced ERK activation. We identify NRP1 as a novel substrate of MT4-MMP and demonstrate that MT4-MMP-mediated NRP1 cleavage restricts NRP1 surface availability to tune the intensity of VEGFA signaling. Furthermore, pharmacological blockade of VEGFA-NRP1 binding partially rescues the vascular defects caused by endothelial MT4-MMP loss in vivo. Together, these findings uncover the MT4-MMP/NRP1 axis as a pivotal control point that prevents aberrant vessel expansion, establishing membrane-anchored proteolysis as a primary regulator across developmental and reparative contexts. TeaserThe proteolytic constraint exerted by MT4-MMP dictates neurovascular development and wound repair through the spatial control of NRP1-VEGFA signaling.

cell biology↗

bioRxiv2026

Butyrate extends health and lifespan in mice with mitochondrial deficiency

Mitochondrial diseases progressively lead to multisystemic failure with treatment options remaining extremely limited. To investigate novel strategies that alleviate mitochondrial dysfunction, we have generated an ubiquitous and tamoxifen-inducible knockout mouse model of mitochondrial transcription factor A (TFAM), a nuclear-encoded protein involved in mitochondrial DNA (mtDNA) maintenance -- Tfamfl/flUbCre-ERT2 (iTfamKO) mice. Systemic TFAM deficiency triggers mitochondrial decline in a myriad of tissues in adult mice. Consequently, iTfamKO mice manifest multiorgan dysfunction including lipodystrophy, sarcopenia, metabolic alterations, kidney failure, neurodegeneration, and locomotor dysregulation, which result in the premature death of these mice. Interestingly, iTfamKO mice display intestinal barrier disruption and gut dysbiosis, with diminished levels of microbiota-derived short-fatty acids (SCFAs), such as butyrate. Mice with a deficient proof-reading version of the mtDNA polymerase gamma (mtDNA-mutator mice) phenocopy the dysfunction of the intestinal barrier and bacterial dysbiosis with reduced levels of butyrate, suggesting that different mouse models of mitochondrial dysfunction share deficient generation of butyrate. Transfer of microbiota from healthy control mice or administration of tributyrin, a butyrate precursor, delay multiple signs of multimorbidity extending lifespan in iTfamKO mice. Mechanistically, butyrate supplementation recovers epigenetic histone acylation marks that are lost in the intestine of Tfam deficient mice. Overall, our findings highlight the relevance of preserving host-microbiota symbiosis in disorders related to mitochondrial dysfunction.

molecular biology↗