Syntaphilin puts the brakes on axonal mitochondria

M itochondria move around inside neurons to make sure they localize to whichever part of these highly polarized cells they are needed in. For example, mitochondria accumulate in active synapses to facilitate synaptic transmission by providing energy and buffering calcium levels. Chen and Sheng describe how the organelles are immobilized in response to synaptic activity (1). Mitochondria are ferried back and forth along neuronal axons by the microtubule-based motor proteins dynein and kinesin-1. The plus end–directed kinesin motor is coupled to mitochondria by the cargo adaptor Trak1 or Trak2 and the calcium-sensing protein Miro. In 2009, two papers revealed that, if motile mitochondria pass an active synaptic terminal, the local increase in calcium levels disrupts the Miro– Trak–kinesin complex and arrests the mito-chondria at the synapse (2, 3). The papers disagreed, however, as to whether kinesin remained associated with stationary mito-chondria (3) or whether the motor was completely decoupled from the organelle upon immobilization (2). Around the same time, Zu-Hang Sheng and colleagues at the National Institute of Neurological Disorders and Stroke in Bethesda, Mary-land, identifi ed syntaphilin (SNPH) as another major regulator of axonal mitochon-drial motility (4). Axonal mi-tochondria are more mobile in neurons lacking SNPH, an axonal mitochondrial membrane protein that anchors the organelle by binding to micro-tubules. Postdoc Yanmin Chen subsequently discovered that axonal mitochondria aren't arrested by activity-triggered Ca 2+ infl ux in SNPH-null neurons (1). " The mitochondria keep moving upon increased neuronal fi ring , " explains Sheng. " The striking dynamics were a real surprise and suggested that SNPH is required for the activity-dependent immobilization of axonal mitochondria. " Chen and Sheng discovered that SNPH bound directly to the kinesin heavy chain KIF5 and that this interaction was required to immobilize mitochondria in response to synaptic activity. Moreover, SNPH competed with the Trak2 adaptor for KIF5's C terminus. Synaptic activity and elevated calcium levels favored the interaction between SNPH and KIF5 by disrupting the Miro– Trak–kinesin complex. In addition, sustained neuronal activity increased SNPH's recruitment to axonal mitochondria. But the SNPH–KIF5 interaction maintains kinesin-1's attachment to mitochon-dria, so how does a switch in KIF5 binding partners lead to the activity-dependent immobilization of the organelle? One mechanism may involve SNPH's microtubule-binding capacity, which could anchor mitochondria onto microtubules, thus serving as a molecular brake to stop both anterograde trafficking by kinesin-1 and retrograde transport by the minus end–directed motor dynein. However, Chen and Sheng …