Mitochondrial Motility

Identification: Schwarz, Thomas


Description

Mitochondrial Motility
 
Thomas L. Schwarz
Boston Children's Hospital and Harvard Medical School
 
Mitochondria in metazoan cells undergo microtubule-based transport that serves to distribute mitochondria according to local needs. In neurons, whose axons may extend for up to a meter in humans, mitochondrial motility has a particularly critical function. In the course of studying how PINK1 functions in the mitophagy of axonal mitochondria, we uncovered a novel function for mitochondrial motility - the transport of selected mRNA into axons and dendrites. The extremely short half-life of PINK1 protein is incompatible with its transport down long axons and instead requires local axonal synthesis. We find that PINK1 mRNA, as well as other transcripts for mitochondrial proteins and actively translating ribosomes, are selectively localized on the mitochondrial surface and depend on mitochondrial movement for entry into the axon.
The motor/adaptor complex that mediates mitochondrial motility in metazoan cells consists of Miro (RhoT1/2,) which is anchored in the OMM, and Milton (TRAK1/2), an adaptor for recruitment of the Kinesin and the dynein/dynactin complex.  Onto this core machinery, extensive regulation has been layered. Previously, we and others have found that the PINK1/Parkin pathway arrests mitochondrial movement, potentially as an early step towards mitophagy of damaged mitochondria. We recently uncovered an additional mechanism for arresting mitochondria by anchoring them to the actin cytoskeleton. In response to increases in glucose availability, Milton undergoes GlcNAcylation by O-GlcNAc Transferase. This modification recruits the actin-associated protein FHL2 and thereby arrests mitochondrial movement in both neuronal and non-neuronal cells.  
To identify additional regulators of mitochondrial transport, we have undertaken a high-resolution imaging-based screen for small molecules that can enhance their motility in rat hippocampal axons. This screen has identified two novel cellular targets. Inhibition of these targets can alleviate defects in mitochondrial motility in a cellular model of ALS, motor neurons derived from human iPSCs carrying a SOD1 mutation.

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