A Stress-Responsive Nuclear Factor, GLDI-8, Mediates Mitochondrial Stress Responses to ETC Dysfunction

Mitochondrial electron transport chain (ETC) impairment triggers mitochondrial unfolded protein response (UPR^mt) that promotes mitochondrial homeostasis, yet the nuclear factors that mediate these responses remain incompletely defined. Here, we identify GLDI-8 as a nuclear factor required for robust activation of the hsp-6p::gfp UPR^mt reporter induced by ETC dysfunction in Caenorhabditis elegans. Depletion of gldi-8 markedly compromises mitochondrial stress-induced hsp-6p::gfp reporter activation, and transgenic rescue restores the response, supporting a specific requirement for GLDI-8 in this pathway. Mitochondrial stress promotes nuclear accumulation of GLDI-8; however, a GLDI-8 transcriptional (promoter) reporter shows no detectable induction under the same conditions, suggesting that regulation occurs at the post-transcriptional level. Genetic analysis further shows that stress-induced nuclear translocation of GLDI-8 is not abolished by atfs-1 knockdown, and GLDI-8 is dispensable for DVE-1 nuclear translocation under mitochondrial stress. Together, these findings establish GLDI-8 as a mitochondrial stress-responsive nuclear factor that contributes to ETC impairment-induced transcriptional responses and adds to the complex regulatory network underlying the UPR^mt.