Aberrant TIMM8B alternative splicing compromises mitochondrial respiratory chain integrity and redox homeostasis

Mitochondrial redox homeostasis depends on respiratory chain integrity, but whether environmental stress alters this system through alternative splicing remains poorly understood. Here, we identify aberrant TIMM8B alternative splicing as a post-transcriptional mechanism that compromises mitochondrial respiratory chain function and redox homeostasis. Using perfluoroundecanoic acid (PFUnDA) as an environmental stressor, transcriptomic profiling of HaCaT cells revealed suppression of mitochondrial bioenergetic programs, including oxidative phosphorylation, the tricarboxylic acid cycle, mitochondrial central dogma, and protein import. Splicing analysis identified TIMM8B exon 1a inclusion as a prominent stress-associated event, which was validated by RT-PCR. The exon 1a-included isoform showed reduced transcript stability and markedly reduced detectable protein abundance. Functionally, PFUnDA impaired mitochondrial respiration in HaCaT and HDF cells. TIMM8B isoform-function analysis further showed that the exon 1a-included isoform failed to preserve ETC activity, mitochondrial membrane potential, and MitoSOX-associated redox signal, whereas the exon 1a-excluded isoform partially restored these mitochondrial readouts toward basal levels. In zebrafish, PFUnDA reduced mitochondrial fluorescence and induced NAC-sensitive oxidant accumulation. Collectively, these findings identify aberrant TIMM8B alternative splicing as a mechanism linking environmental stress to mitochondrial respiratory chain dysfunction and redox dysregulation.