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Integrated mitochondrial profiling identifies mitochondrial gene expression and membrane potential in IL-4/IL-13 macrophages

ABSTRACT: Macrophage activation triggers intense genetic and immunometabolic reprograming that support distinct macrophage functions, and mitochondria are central to this process. To date, the extent to which they are remodeled and how this impacts macrophage function remains unclear. Here, we integrate transcriptomics with whole-cell and highly purified mitochondrial proteomics to profile LPS/IFNγ- andIL-4/IL-13-stimulated bone-marrow–derived macrophages (BMDM). We uncover a striking disconnect between mitochondrial transcripts and proteins and identify a STAT6-dependent increase in mitochondrial gene expression and intramitochondrial translation as hallmarks of IL-4/IL-13 stimulation. Pharmacological blockade of mitochondrial translation or individual respiratory chain complexes impairs activation, while ATP synthase inhibition uniquely triggers mitochondrial hyperpolarization and the integrated stress response, halting IL-4/IL-13 activation. Restoring mitochondrial membrane potential or inhibiting the stress response rescues effector synthesis. Together, we establish mitochondrial gene expression and membrane potential as regulators of macrophage immunometabolism and identify mitochondrial translation as a critical, drug-sensitive determinant of IL-4/IL-13 macrophage function.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Bone Marrow, Macrophage

SUBMITTER: Alexis Jourdain

LAB HEAD: Alexis Jourdain

PROVIDER: PXD069191 | Pride | 2026-06-29

REPOSITORIES: Pride

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			Action	DRS
	3580_6-7-2022_Blanco_14590_DIA_140min_5ul_RB1.d.zip	Other
	3581_6-7-2022_Blanco_14593_DIA_140min_5ul_RB2.d.zip	Other
	3582_6-7-2022_Blanco_14596_DIA_140min_5ul_RB3.d.zip	Other
	3583_6-7-2022_Blanco_14599_DIA_140min_5ul_RB4.d.zip	Other
	3586_6-7-2022_Blanco_14591_DIA_140min_5ul_RB5.d.zip	Other

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Integrated mitochondrial profiling identifies mitochondrial gene expression and membrane potential in IL-4/IL-13 macrophages

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