MTR4: A Conserved Youth Factor for Vascular Endothelium.

Abstract

Vascular endothelial cell (VEC) senescence drives organismal aging and age-related pathologies, yet the intrinsic factors preserving endothelial youthfulness remain poorly defined. Here, we identify MTR4, an evolutionarily conserved RNA helicase and nuclear RNA exosome cofactor, as a novel regulator of VEC senescence. MTR4 protein declines markedly in senescent HUVECs and aged mouse aortas, independent of general cell cycle exit. Mechanistically, senescence-induced upregulation of the E3 ubiquitin ligase synoviolin 1 (SYVN1) promotes K638-linked ubiquitination and proteasomal degradation of MTR4. MTR4 depletion drives proliferating HUVECs into premature senescence, whereas its overexpression restores a youthful phenotype in senescent cells by binding BUB3 to stabilize BUB3 and sustain BUBR1 expression. In mice, endothelial Mtr4 knockdown promotes vascular dysfunction and multi-organ aging, while endothelium-specific Mtr4 overexpression alleviates these phenotypes. In C. elegans, mtr-4 overexpression dramatically extends lifespan, comparable to classic longevity models and surpassing most single-gene interventions, while its knockdown accelerates aging. Our findings establish MTR4 as a critical guardian of endothelial homeostasis and organismal aging, with strong translational potential for mitigating age-related vascular dysfunction.