A genetic program boosts mitochondrial function to power macrophage tissue invasion

Abstract

Metabolic adaptation to changing demands underlies homeostasis. During inflammation or metastasis, cells leading migration into challenging environments require an energy boost, however what controls this capacity is unknown. We identify a previously unstudied nuclear protein, Atossa, as changing metabolism in Drosophila melanogaster immune cells to promote tissue invasion. Atossa's vertebrate orthologs, FAM214A-B can fully substitute for Atossa, indicating functional conservation from flies to mammals. Atossa increases mRNA levels of Porthos, an unstudied RNA helicase and two metabolic enzymes, LKR/SDH and GR/HPR. Porthos increases translation of a gene subset, including those affecting mitochondrial functions, the electron transport chain, and metabolism. Respiration measurements and metabolomics indicate that Atossa and Porthos power up mitochondrial oxidative phosphorylation to produce sufficient energy for pioneer macrophages to forge a path into tissues. As increasing oxidative phosphorylation enables many crucial physiological responses, this unique genetic program may modulate a wide range of cellular behaviors beyond migration.

A translation control module coordinates germline stem cell differentiation with ribosome biogenesis duringDrosophilaoogenesis

“…Although it is also possible that phenotypic differences arise from a common molecular cause, our data suggests two sources of potential tissue specificity: 1) tissues express different cohorts of mRNAs, such as Non1, that are sensitive to ribosome levels. For example, we find that in Drosophila macrophages, RNAs that regulate the metabolic state of macrophages and influence their migration require increased levels of ribosomes for their translation (Emtenani et al, 2021). 2) p53 activation, as has been previously described, is differentially tolerated in different developing tissues (Bowen and Attardi, 2019;Calo et al, 2018;Jones et al, 2008).…”

Cell division in tissues enables macrophage infiltration

“…The edge of these tissues represents a barrier that macrophages must overcome in order to invade, and the first macrophage requires around 20 min to enter after reaching this location. Macrophage-specific programs, not involving proteolytic ECM degradation 8 , are known to affect the efficiency of macrophage entry [21][22][23] . However, how the dynamics and properties of surrounding cells influence macrophage tissue invasion remains unclear 9 .…”