KLP6: a newly identified kinesin that regulates the morphology and transport of mitochondria in neuronal cells

Abstract

Mitochondria utilize diverse cytoskeleton-based mechanisms to control their functions and morphology. Here, we report a role for kinesin-like protein KLP6, a newly identified member of the kinesin family, in mitochondrial morphology and dynamics. An RNA interference screen using Caenorhabditis elegans led us to identify a C. elegans KLP-6 involved in maintaining mitochondrial morphology. We cloned a cDNA coding for a rat homolog of C. elegans KLP-6, which is an uncharacterized kinesin in vertebrates. A rat KLP6 mutant protein lacking the motor domain induced changes in mitochondrial morphology and significantly decreased mitochondrial motility in HeLa cells, but did not affect the morphology of other organelles. In addition, the KLP6 mutant inhibited transport of mitochondria during anterograde movement in differentiated neuro 2a cells. To date, two kinesins, KIF1Bα and kinesin heavy chain (KHC; also known as KIF5) have been shown to be involved in the distribution of mitochondria in neurons. Expression of the kinesin heavy chain/KIF5 mutant prevented mitochondria from entering into neurites, whereas both the KLP6 and KIF1Bα mutants decreased mitochondrial transport in axonal neurites. Furthermore, both KLP6 and KIF1Bα bind to KBP, a KIF1-binding protein required for axonal outgrowth and mitochondrial distribution. Thus, KLP6 is a newly identified kinesin family member that regulates mitochondrial morphology and transport.

Mitochondrial Trafficking in Neurons

“…This family of motors is, however, critical for the transport of synaptic vesicle precursors (Hall and Hedgecock 1991;Yonekawa et al 1998;Pack-Chung et al 2007;Barkus et al 2008). A distantly related member of the Kinesin-3 family, kinesin-like protein 6 (KLP6), was found to alter mitochondrial shape in Caenorhabditis elegans and mitochondrial motility in HeLa cells and a neural cell line (Tanaka et al 2011) when mutated or knocked down with RNA interfer-ence (RNAi). Whereas loss of the conventional kinesin heavy chain prevented mitochondria from entering axons at all, mutant forms of KLP6 and Kif1Ba altered the velocity of axonal mitochondria (Tanaka et al 2011).…”

“…A distantly related member of the Kinesin-3 family, kinesin-like protein 6 (KLP6), was found to alter mitochondrial shape in Caenorhabditis elegans and mitochondrial motility in HeLa cells and a neural cell line (Tanaka et al 2011) when mutated or knocked down with RNA interfer-ence (RNAi). Whereas loss of the conventional kinesin heavy chain prevented mitochondria from entering axons at all, mutant forms of KLP6 and Kif1Ba altered the velocity of axonal mitochondria (Tanaka et al 2011). Both of these Kinesin-3 motors have been shown to bind to a candidate adaptor protein, the kinesin binding protein (KBP).…”

The axonal transport of mitochondria

“…Long-distance movement of mitochondria in axons is driven by kinesin and dynein motors along microtubules that are arranged with their plus ends toward synaptic terminals (Figs 1, 2). Function inhibition and biochemical studies indicate that kinesin-1 is the primary anterograde mitochondrial motor (Barkus et al, 2008;Pilling et al, 2006;Vale et al, 1985), but there is evidence from studies of tissue culture cells that the kinesin-3 motors Kif1b and Klp6 also can transport mitochondria and thus might do so in axons (Nangaku et al, 1994;Tanaka et al, 2011). Similar approaches indicate that cytoplasmic dynein is the primary retrograde mitochondrial motor (Pilling et al, 2006;Schnapp and Reese, 1989).…”

Brain-derived Neurotrophic Factor (BDNF)-induced Mitochondrial Motility Arrest and Presynaptic Docking Contribute to BDNF-enhanced Synaptic Transmission

“…In vivo and in vitro studies have identified several kinesin family members, including KIF5A/B/C, KIF1B␣, and KLP6, that are involved in mitochondrial anterograde transport (3)(4)(5)(6)(7). In addition to the motor proteins, intracellular signaling pathways that regulate mitochondrial movement have also been investigated.…”