TIM8 Deficiency in Yeast Induces Endoplasmic Reticulum Stress and Shortens the Chronological Lifespan

Yeast <i>TIM8</i> was initially identified as a homolog of human TIMM8A/DDP1, which is associated with human deafness-dystonia syndrome. Tim8p is located in the mitochondrial intermembrane space and forms a hetero-oligomeric complex with Tim13p to facilitate protein transport through the TIM22 translocation system. Previous research has indicated that <i>TIM8</i> is not essential for yeast survival but does affect the import of Tim23p in the absence of the Tim8-Tim13 complex. Previous research on <i>TIM8</i> has focused mainly on its involvement in the mitochondrial protein transport pathway, and the precise biological function of <i>TIM8</i> remains incompletely understood. In this study, we provide the first report that yeast <i>TIM8</i> is associated with the endoplasmic reticulum (ER) stress response and chronological senescence. We found that deletion of <i>TIM8</i> leads to both oxidative stress and ER stress in yeast cells while increasing resistance to the ER stress inducer tunicamycin (TM), which is accompanied by an enhanced basic unfolded protein response (UPR). More importantly, <i>TIM8</i> deficiency can lead to a shortened chronological lifespan (CLS) but does not affect the replicative lifespan (RLS). Moreover, we found that improving the antioxidant capacity further increased TM resistance in the <i>tim8Δ</i> strain. Importantly, we provide evidence that the knockdown of TIMM8A in ARPE-19 human retinal pigment epithelium cells can also induce ER stress, suggesting the potential function of the <i>TIM8</i> gene in ER stress is conserved from budding yeast to higher eukaryotes. In summary, these results suggest novel roles for <i>TIM8</i> in maintaining ER homeostasis and CLS maintenance.