A Mitochondria–Lysosome Transport Pathway

RESEARCH HIGHLIGHTS

Controlling enteric nerve Interestingly, inhibition of integrin signalling The authors used point mutations to establish cell migration or ROCK activity rescued directed migration of that residue Met 44 of actin was essential for the MEFs and normalized the migration of ENCCs F-actin-severing function of Mical. Manipulation A functional gastrointestinal system is in organ cultures. Although the precise function of Mical levels is known to generate abnormal dependent on the enteric nervous system, of Phactr4 remains to be discovered, these data bristle cell processes in Drosophila. In the present which is formed during embryogenesis through demonstrate its role in regulating lamellipodial study, mutation of the Met 44 actin residue colonization of the gut by enteric neural crest actin dynamics through cofilin activity suppressed Mical overexpression phenotypes cells (ENCCs). Now, Niswander and colleagues controlled by integrin and PP1 signalling. CKR and phenocopied Mical loss-of-function effects identify the protein phosphatase 1 (PP1)- and in Drosophila. Together, these findings establish actin-binding protein Phactr4 as a regulator actin as a direct substrate of Mical and reveal of directional and collective ENCC migration a specific oxidation-dependent mechanism (Genes Dev. 26, 69–81; 2012). Actin gets the oxidation to regulate actin filament dynamics and cell Analysis of mouse embryos expressing treatment from Mical processes in vivo. AIZ a Phactr4 mutation known to abolish PP1 binding revealed reduced enteric neuronal Mical, an enzyme mediating redox reactions, numbers and defective organization at is known to promote actin remodelling embryonic day 18.5, and reduced ENCC in response to semaphorin signalling by A mitochondria–lysosome numbers in the gut at earlier stages (E12.5). disassembling actin filaments. However, the transport pathway These defects were not due to defective ENCC precise mechanism of Mical-dependent F-actin specification, proliferation or differentiation. disassembly and the identity of Mical substrates Reactive oxygen species (ROS) that arise Instead, time-lapse imaging of hindgut organ have remained obscure. Hung et al. now report from electron transport chain activity can be explants revealed disrupted directional that Mical enzymatically modifies a specific neutralized by oxidation of mitochondrial migration of ENCCs and detachment of cells actin residue to promote F-actin severing proteins and lipids. However, the way these from the wave front. Inhibition of PP1 caused (Science 334, 1710–1713; 2011). oxidized macromolecules are removed from similar migration defects in wild-type organ Using in vitro biochemical assays and the mitochondria is not clear. McBride and cultures. In wound healing assays, mutant microscopy techniques, the authors colleagues now show that a subpopulation of mouse embryonic fibroblasts (MEFs) displayed demonstrated that F-actin activates the enzymatic mitochondria-derived vesicles (MDVs) that randomized actin protrusion and migration activity of Mical to promote actin filament are generated in response to oxidative stress are directions, and reduced lamellipodia size. severing and prevent repolymerization by stably delivered to lysosomes (Curr. Biol. doi:10.1016/j. Phactr4 co-localized with the actin regulator and specifically modifying actin subunits at cub.2011.11.057; 2012). These MDVs might cofilin and integrin-β1 at lamellipodia tips, methionines 44 and 47 through the addition of therefore be an important transport intermediate and mutant cells displayed a ROCK-kinase- oxygen. Based on previous knowledge of actin for degrading oxidized mitochondrial proteins. dependent increase in phosphorylation of structure, these modifications were predicted to McBride and colleagues found that MDVs cofilin and increased integrin-β1 signalling. affect the interaction between F-actin subunits. were generated in mammalian cell lines as an early response to oxidative stress. Most of Aggregation is key for chimeric monkeys these structures contained the mitochondrial When injected into host mouse blastocysts, mouse pluripotent embryonic stem cells (ESCs) outer membrane protein Tom20, but lacked derived from the inner cell mass (ICM) of the embryo, or induced pluripotent cells obtained inner-membrane proteins or matrix-associated through reprogramming of somatic cells, can contribute to the formation of all host tissues. proteins. MDV formation did not require Although the preparation of chimera is well-established in mice, it had not yet been achieved the GTPase Drp1 or the autophagy protein in primates. Mitalipov and colleagues demonstrate that aggregation of the totipotent blas- ATG5, and the MDVs did not co-localize with tomeres of several early dividing Rhesus monkey embryos can successfully yield chimeric autophagosome marker LC3. This indicates monkeys (Cell doi:10.1016/j.cell.2011.12.007; 2012). that MDV formation is independent of the In initial experiments, monkey ESCs injected into blastocysts could not incorporate into mitochondrial fission or mitophagy machinery. the host foetuses, indicating a failure of host blastocysts to sustain ESC maintenance. Injected The authors then traced the movement of these isolated ICMs were also unable to integrate into the host foetuses but could successfully form stress-induced MDVs and found that they their own foetus, participate in shared extraembryonic tissue and develop some degree of chimerism with host embryos (mainly in the liver and spleen, perhaps due to the sharing of were delivered to multivesicular bodies, which blood derivatives). Analysis of developmental markers suggested that lineage determination went on to fuse with lysosomes. Together, these had started in the monkey ICMs, which may have diminished their plasticity and impeded data suggest the existence of a stress-induced their integration into host foetuses. The authors finally allowed several early dividing and mitochondria–lysosome transport pathway totipotent embryos to aggregate before injection. They obtained foetuses displaying a high that might mediate removal of damaged degree of chimerism, and healthy chimeric monkeys were born. Interestingly, this set of mitochondrial proteins. EJC experiments suggests that it would be difficult to use primate embryos as hosts to test pluri- potency by direct injection of candidate pluripotent cells, as cleaving primate embryos does By Emily J. Chenette, Christina Karlsson Rosenthal, not seem to provide a niche for the maintenance of ESCs. NLB Nathalie Le Bot and Alexia-Ileana Zaromytidou

130 NATURE CELL BIOLOGY VOLUME 14 | NUMBER 2 | FEBRUARY 2012