Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to Prostaglandin E2

Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here, we show that PGE2 caused mitochondrial membrane potential (Delta psi(m)) to dissipate in interleukin-4-activated (M(IL-4)) macrophages. Effects on Delta psi(m) were a consequence of PGE2-initiated transcriptional regulation of genes, particularly Got1, in the malateaspartate shuttle (MAS). Reduced Delta psi(m) caused alterations in the expression of 126 voltage-regulated genes (VRGs), including those encoding resistin-like molecule a (RELM alpha), a key marker of M(IL-4) cells, and genes that regulate the cell cycle. The transcription factor ETS variant 1 (ETV1) played a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Delta psi(m)-sensitive transcription factor and Delta psi(m) as amediator of mitochondrial-directed nuclear gene expression.