Macrophage mitochondrial bioenergetics and tissue invasion are boosted by an Atossa‐Porthos axis in Drosophila

Abstract

Cellular metabolism must adapt to changing demands to enable homeostasis. During immune responses or cancer metastasis, cells leading migration into challenging environments require an energy boost, but what controls this capacity is unclear. Here, we study a previously uncharacterized nuclear protein, Atossa (encoded by CG9005), which supports macrophage invasion into the germband of Drosophila by controlling cellular metabolism. First, nuclear Atossa increases mRNA levels of Porthos, a DEAD-box protein, and of two metabolic enzymes, lysineα-ketoglutarate reductase (LKR/SDH) and NADPH glyoxylate reductase (GR/HPR), thus enhancing mitochondrial bioenergetics. Then Porthos supports ribosome assembly and thereby raises the translational efficiency of a subset of mRNAs, including those affecting mitochondrial functions, the electron transport chain, and metabolism. Mitochondrial respiration measurements, metabolomics, and live imaging indicate that Atossa and Porthos power up OxPhos and energy production to promote the forging of a path into tissues by leading macrophages. Since many crucial physiological responses require increases in mitochondrial energy output, this previously undescribed genetic program may modulate a wide range of cellular behaviors.

Atossa : a royal link between OXPHOS metabolism and macrophage migration

“…Anchor cells may create an cellular microenvironment enriched with glucose receptors, glycolytic enzymes and mitochondria that would energetically support the migration at the tip of the protrusions, which appears to align with the results reported by Emtenani et al (2022). These findings might reconcile the duality between glycolysis (Guak & Krawczyk, 2020) and OXPHOS (Emtenani et al , 2022; Garde et al , 2022) dependency during invasion indicating that cells undergo spatially focalized metabolic switches within the same cell to promote invasion and migration. While further studies in mammals need to validate the implications and dynamics of Atossa in controlling immune or other tissue responses under energetic demands, these studies identify a regulatory process orchestrated from the nucleus between mitochondrial bioenergetics and macrophage function.…”

“…Overall, Emtenani et al (2022) provide novel and interesting findings on switching the balance between OXPHOS and glycolysis during immune responses. The authors show a novel regulatory axis initiated by Atossa that synchronizes transcriptional and translational programmes to promote macrophage invasion of tissues.…”

“…The ability of immune cells to penetrate affected tissues is highly dependent on energy provided by mitochondria, yet their involvement in promoting migration remains unclear. Recent work by Emtenani et al (2022) describes a nuclear Atossa-Porthos axis that adjusts transcription and translation of a small subset of OXPHOS genes to increase mitochondrial bioenergetics and allow macrophage tissue invasion in flies.…”

PSC niche develops into immune-responsive blood cells capable of transdifferentiating into lamellocytes inDrosophila

“…OxPhos-PL show a striking increased expression of several genes involved in mitochondrial oxidative phosphorylation system (OXPHOS, figure 3G, H). This cluster also specifically expresses several ribosomal proteins (Figure 3G) which might reflect an important cross-regulatory mechanism between mitochondrial energy production and increased ribosomal assembly and translation as recently described for macrophage tissue invasion in the Drosophila embryo 51 . For professional phagocytes, sufficient ATP as the critical energy source is even required to drive endocytic and phagocytic processes, especially at the onset of metamorphosis when plasmatocytes encounter and clear apoptotic cells from massive larval tissue histolysis.…”

Cell division in tissues enables macrophage infiltration

“…This first macrophage requires ~20 min to enter through the tissue barrier, using αPS2 - and βPS-integrins that bind to laminin ( 9 , 10 ). Matrix metalloproteolytic ECM degradation does not affect the efficiency of entry ( 10 ) but macrophage-specific programs do ( 11 – 13 ). How the dynamics and properties of surrounding cells influence macrophage tissue invasion remains unclear.…”