Cells function as highly structured ecosystems in which organelles act as interdependent, communicative units whose coordinated interactions and dynamic repositioning sustain cellular health. Live-cell neuronal imaging shows that mitochondria and lysosomes undergo directed, stimulus-dependent trafficking, consistent with regulated organelle agency.
We hypothesize that an underlying rationale for this agency is the activity of organelle surface–associated RNAs (OSRs), in which RNA granules dock onto organelle membranes, so that the organelles to act as “taxis” that transport defined RNA cohorts to subcellular destinations such as neuronal synapses. At these sites, OSRs may be released and locally translated to regulate local organelle function, organelle–organelle interactions, and site-specific cellular biology. Bulk-cell approaches obscure these spatially encoded processes by averaging across heterogeneous cell states and eliminating subcellular context.
To overcome this limitation, we developed the RNA Cargo Interrogator (RCI), which identifies RNAs localized to specific organelle surfaces in situ at single-cell and single-organelle resolution in human neurons. Leveraging the vectorial nature of RCI readouts, we will define conserved RNA sequence and structural motifs that recruit RNAs to organelle membranes. These motifs will be functionally tested to identify the encoded intracellular targeting logic—RNA “addresses” governing organelle-specific retention, transport, and release—that can be engineered into heterologous RNAs to enable stimulus-driven subcellular targeting via organelle movement.
Together, these studies establish organelle/OSR trafficking as a fundamental regulatory layer linking RNA localization, organelle dynamics, and neuronal plasticity, redefining organelle–RNA association as a programmable determinant of cell function and providing a new mechanistic entry point for modulating subcellular pathways relevant to neurological disease.
