Mitochondrial trafficking and redox/phosphorylation signaling supporting cell migration phenotypes.

Regulation of cell signaling cascades is critical in making sure the response is activated spatially and for a desired duration. Cell signaling cascades are spatially and temporally controlled through local protein phosphorylation events which are determined by the activation of specific kinases and/or inactivation of phosphatases to elicit a complete and thorough response. For example, A-kinase-anchoring proteins (AKAPs) contribute to the local regulated activity protein kinase A (PKA). The activity of kinases and phosphatases can also be regulated through redox-dependent cysteine modifications that mediate the activity of these proteins. A primary example of this is the activation of the epidermal growth factor receptor (EGFR) and the inactivation of the phosphatase and tensin homologue (PTEN) phosphatase by reactive oxygen species (ROS). Therefore, the local redox environment must play a critical role in the timing and magnitude of these events. Mitochondria are a primary source of ROS and energy (ATP) that contributes to redox-dependent signaling and ATP-dependent phosphorylation events, respectively. The strategic positioning of mitochondria within cells contributes to intracellular gradients of ROS and ATP, which have been shown to correlate with changes to protein redox and phosphorylation status driving downstream cellular processes. In this review, we will discuss the relationship between subcellular mitochondrial positioning and intracellular ROS and ATP gradients that support dynamic oxidation and phosphorylation signaling and resulting cellular effects, specifically associated with cell migration signaling.

Local recruitment and fueling of the cellular powerplant to support cell invasion.

In this issue of Developmental Cell, Garde et al. demonstrate that polarized expression of the glucose transporter FGT-1, accompanied by a localized glucose gradient and mitochondrial recruitment to the basal membrane of the anchor cell (AC), supports localized ATP generation required for basement membrane (BM) invasion in C. elegans.

Miro1-mediated mitochondrial positioning supports subcellular redox status.

Mitochondria are strategically trafficked throughout the cell by the action of microtubule motors, the actin cytoskeleton and adapter proteins. The intracellular positioning of mitochondria supports subcellular levels of ATP, Ca2+ and reactive oxygen species (ROS, i.e. hydrogen peroxide, H2O2). Previous work from our group showed that deletion of the mitochondrial adapter protein Miro1 leads to perinuclear clustering of mitochondria, leaving the cell periphery devoid of mitochondria which compromises peripheral energy status. Herein, we report that deletion of Miro1 significantly restricts subcellular H2O2 levels to the perinuclear space which directly affects intracellular responses to elevated mitochondrial ROS. Using the genetically encoded H2O2-responsive fluorescent biosensor HyPer7, we show that the highest levels of subcellular H2O2 map to sites of increased mitochondrial density. Deletion of Miro1 or disruption of microtubule dynamics with Taxol significantly reduces peripheral H2O2 levels. Following inhibition of mitochondrial complex 1 with rotenone we observe elevated spikes of H2O2 in the cell periphery and complementary oxidation of mitochondrial peroxiredoxin 3 (PRX3) and cytosolic peroxiredoxin 2 (PRX2). Conversely, in cells lacking Miro1, rotenone did not increase peripheral H2O2 or PRX2 oxidation but rather lead to increased nuclear H2O2 and an elevated DNA-damage response. Lastly, local levels of HyPer7 oxidation correlate with the size and abundance of focal adhesions (FAs) in MEFs and cells lacking Miro1 have significantly smaller focal adhesions and reduced phosphorylation levels of vinculin and p130Cas compared to Miro1+/+ MEFs. Together, we present evidence that the intracellular distribution of mitochondria influences subcellular H2O2 levels and local cellular responses dependent on mitochondrial ROS.

ERP differences in processing canonical and noncanonical finger-numeral configurations.

Finger-numeral configurations are used to represent numerosities, to count, and to do arithmetic across cultures. Previous research has distinguished between two forms of finger-numeral configurations; finger montring and finger counting. Montring refers to how people raise their fingers to show numerosities to others and usually serves a communicative function. Finger counting is used both for counting and arithmetic, and has a self-directed, facilitative function. In this study we compared the ERP markers for recognition of montring, counting, and noncanonical finger-numeral configurations with adult participants to explore differences in early perceptual and later semantic processing. Montring configurations were recognized faster and more accurately compared to counting and noncanonical. Recognition of montring configurations drew larger attentional resources, marked by higher positivity in the P1/N1 range, and montring and counting showed similar patterns of semantic processing, marked by higher positivity in the P3 range compared to noncanonical, possibly due to strategy differences (memory recall vs. counting). We also found some ERP evidence for participants' finger counting habits affecting their processing of counting configurations. Overall, the results show differences in perceptual and semantic processes involved in extracting numerical information across the three finger-numeral configurations.