Neuronal mitochondria transport Pink1 mRNA via Synaptojanin 2 to support local mitophagy

Abstract

PTEN-induced kinase 1 (PINK1) is a very short-lived protein that is required for the removal of damaged mitochondria through Parkin translocation and mitophagy. Because the short half-life of PINK1 limits its ability to be trafficked into neurites, local translation is required for this mitophagy pathway to be active far from the soma. The Pink1 transcript is associated with and cotransported with neuronal mitochondria. In concert with translation, the mitochondrial outer membrane protein Synaptojanin 2 binding protein (SYNJ2BP) and Synaptojanin 2 (SYNJ2) are required for tethering Pink1 mRNA to mitochondria via an RNA-binding domain in SYNJ2. This neuron-specific adaptation for local translation of PINK1 provides distal mitochondria with a continuous supply of PINK1 for activation of mitophagy.

The PINK1 repertoire: Not just a one trick pony

“…PINK1 mRNA hitches a ride on mitochondria and is transported to distant sites by association with synaptojanin 2 in complex with SYNJ2BP. [75] The nuclear encoded mRNAs for respiratory chain proteins (nRCCs) are specifically repressed in the cytosol. These mRNAs can be recruited to the mitochondrial surface in a manner dependent on TOM20.…”

Linking transport and translation of mRNAs with endosomes and mitochondria

“…Recent findings indicate that organelle co‐transport is important. One example is mRNA hitchhiking on mitochondria as shown for PINK1 mRNA (preprint: Harbauer et al , 2021). As elaborated above, the short‐lived PINK1 protein needs to accumulate on the surface of mitochondria to orchestrate mitophagy.…”

“…Mitochondrial association of the PINK1 mRNA depends on translation as well as the synergistic action of the MTS and sequence elements at the beginning of the ORF. Therefore, mRNA transport in dendrites and axons is achieved (preprint: Harbauer et al , 2021). Interestingly, mitochondrial hitchhiking is not restricted to PINK1 mRNA, as Cox7c mRNA (encoding cytochrome c oxidase subunit 7c; respiration chain complex IV) is also actively transported on the surface of mitochondria in an MTS‐dependent manner in axons (preprint: Cohen et al , 2021).…”

“…However, in vivo the process of mRNA transport appears to be more complex, since (i) higher‐order mRNP transport granules are formed and (ii) alternative membrane‐dependent transport pathways exist (Béthune et al , 2019; preprint: Cohen et al , 2021; preprint: Harbauer et al , 2021, see below). The formation of higher‐order RNP granules in the form of biomolecular condensates is known for neuronal mRNA transport (Brangwynne et al , 2009; Kato & McKnight, 2018).…”

“…Hitchhiking on membrane‐enclosed organelles is an alternative transport mode and has been described for various organelle membranes like ER, mitochondria as well as endosomes (Béthune et al , 2019; preprint: Cohen et al , 2021; preprint: Harbauer et al , 2021; see below). These alternative modes of mRNA transport will be extensively discussed in the remaining part of the review with a special focus on endosomal transport.…”