Abstract: Neurons with their elaborate and extended morphology must employ homeostatic mechanisms that allow neuronal mitochondria to exist far away from the cell body while still retaining a functional proteome.
This process, called “Mitostasis”, is most likely a finely tuned concert of mitochondrial transport, local protein synthesis and local degradation by proteasomal and autophagic mechanisms. Modulation of these processes may prove beneficial in the treatment of neurodegenerative diseases.
However, the processes that allow local translation of mRNAs encoding for mitochondrial proteins are only partially understood. Using the transcript of PTEN-induced kinase 1 (PINK1) as a model substrate, we have discovered that this RNA associates with mitochondria specifically in neurons and uses mitochondria as a means of transport into axons and dendrites. This “mitochondrial hitch-hiking” of mRNAs is a neuron specific mechanism driven by selective expression of an mRNA anchoring complex at the outer mitochondrial membrane. While mitochondria carry the Pink1 mRNA and receive the final protein product, the mRNA can be untethered due to disassembly of the anchoring complex downstream of insulin signaling. The mRNA then relocates to the endolysosomal compartment, whose degradative function is needed for PINK1 synthesis.
The newly synthesized PINK1 precursor needs then to home back to mitochondria, which is enabled by the endoplasmic reticulum-tethered chaperones In the so called ER-SURF pathway, bridging the gap between the site of PINK1 synthesis and import. The entirety of this complex multi-organelle mechanism is necessary for PINK1’s ability to demarcate damaged mitochondria and target them for mitophagy in neurons.