Aging-associated loss of CPEB4 impairs mitochondrial adaptation and promotes stress-induced senescence in alveolar type II cells.

Abstract

Aging is associated with impaired lung repair and increased susceptibility to injury, yet the mechanisms underlying age-associated dysfunction of alveolar type II (AT2) cells remain poorly understood. Although cellular senescence is a hallmark of aging, emerging evidence suggests that aging is also characterized by progressive loss of cellular resilience, rendering epithelial cells increasingly vulnerable to stress. Here, we show that AT2 cells in aged lungs remain predominantly non-senescent under basal conditions but exhibit increased susceptibility to stress-induced senescence. This stress-vulnerable state is accompanied by impaired mitochondrial homeostasis, excessive mitochondrial reactive oxygen species accumulation, and mitochondrial dysfunction. We identify the RNA-binding protein cytoplasmic polyadenylation element-binding protein 4 (CPEB4) as a critical regulator of mitochondrial adaptation in AT2 cells. CPEB4 deficiency does not induce overt senescence under basal conditions but markedly exacerbates stress-induced senescence both in vitro and in vivo. Mechanistically, CPEB4 sustains expression of tumor protein p53-inducible nuclear protein 2 (TP53INP2) through post-transcriptional regulation, thereby preserving mitochondrial homeostasis during stress. Restoration of TP53INP2 partially rescues mitochondrial dysfunction and attenuates senescence-associated phenotypes in CPEB4-deficient cells. Collectively, our findings identify a CPEB4-TP53INP2 axis that preserves mitochondrial adaptability and limits stress-induced senescence, providing mechanistic insight into how aging progressively compromises epithelial stress resilience.