TIA-1 promotes FUNDC1-mediated mitophagy to protect against stress-induced cellular senescence.

Mitochondrial dysfunction, characterized by reduced mitophagy, excessive mitochondrial elongation, and elevated reactive oxygen species production, is a hallmark of cellular senescence. However, the molecular mechanisms linking impairment of redox balance to mitophagy suppression during senescence remain poorly understood. In this study, we identified TIA-1, an RNA-binding protein, as a positive regulator of FUNDC1 expression, a key receptor for ubiquitin-independent mitophagy. Sodium butyrate and ultraviolet-B irradiation triggered oxidative stress-associated senescence in HaCaT cells, leading to reduced TIA-1 expression, decreased FUNDC1 levels, impaired mitophagy flux, excessive mitochondrial elongation, and upregulation of senescence markers. Conversely, ectopic expression of TIA-1 restored FUNDC1 levels, enhanced mitophagy, improved mitochondrial function, and reduced senescence marker expression. Ribonucleoprotein immunoprecipitation assays confirmed that TIA-1 directly interacts with FUNDC1 mRNA, and subsequent analyses indicated that TIA-1 enhances FUNDC1 expression primarily through translational control. Together, these findings establish TIA-1 as a pivotal regulator of mitochondrial homeostasis during cellular stress, acting through FUNDC1 to sustain mitophagy and limit senescence. Targeting TIA-1 may offer new strategies to mitigate mitochondrial dysfunction and restore redox balance in aging and age-related diseases.