Mitochondrial-targeted H₂S delivery elicits broad transcriptional responses in sulfide-adapted fish

Hydrogen sulfide (H₂S) is an environmental toxicant that inhibits cellular energy production in mitochondria. Despite its toxicity, multiple lineages of the freshwater fish Poecilia mexicana (Poeciliidae) have independently colonized and adapted to H₂S-rich springs. Prior studies indicated that gene expression responses to H₂S exposure in both adapted and non-adapted populations extend beyond traditional toxicity targets and enzymatic detoxification pathways, suggesting a complex molecular response. Here, we investigated whether mitochondrial H₂S exposure is sufficient to generate broad transcriptional responses. We used a mitochondria-targeted H₂S donor, AP39, to assess transcriptional responses to mitochondrial-targeted H₂S delivery in gill and liver tissues. Despite mitochondrial targeting, we found strong transcriptional responses, especially in the liver, that extended beyond mitochondrial processes and included pathways associated with cellular stress, metabolism, and transcriptional regulation. These findings demonstrate that mitochondrial-targeted H₂S is sufficient to elicit broad transcriptional responses, consistent with mitochondrial perturbation contributing to the complex molecular response to H₂S.