Tissue-specific consequences of impaired RNA surveillance converge on mitochondrial homeostasis

Here, we investigated the tissue-specific consequences of impaired RNA surveillance using a Drosophila allelic series of the RNA exosome subunit Rrp40. Comparative transcriptomic analyses revealed that neuronal-enriched head tissue and muscle-enriched thorax tissue exhibit largely distinct molecular programs following reduced RNA exosome activity despite disruption of the same RNA surveillance machinery.

Antisense RNAs emerged as particularly sensitive targets of RNA exosome dysfunction and accumulated preferentially in neuronal tissue, indicating enhanced requirements for RNA-level quality control within the nervous system. Although tissue-specific transcriptomic alterations diverged substantially, multiple analyses converged on mitochondrial homeostasis pathways as a common vulnerability. Reduced RNA exosome activity was associated with widespread dysregulation of nuclear-encoded mitochondrial genes, mitochondrial dynamic pathways, and mitochondrial RNA regulatory programs, accompanied by progressive defects in mitochondrial organization, membrane potential, and ATP production.