An inherited mtDNA mutation remodels inflammatory cytokine responses in macrophages and in vivo

Impaired mitochondrial bioenergetics in macrophages can drive
hyperinflammatory cytokine production, but whether this is caused by
inherited mtDNA mutations is unknown. Here, we address this important
question using a multi-omic approach that integrates super-resolution
imaging and metabolic analyses to profile macrophages from a mouse model
of mitochondrial disease caused by a heteroplasmic mutation
(m.5019A>G) in the mitochondrial tRNA for alanine. These
m.5019A>G macrophages exhibit defects in respiratory chain
complexes and oxidative phosphorylation (OxPhos) due to decreased
intra-mitochondrial translation. To adapt to this metabolic stress,
mitochondrial fusion, reductive glutamine metabolism, and aerobic
glycolysis are all increased. Upon inflammatory activation, type I
interferon (IFN-I) release is enhanced, while the production of
pro-inflammatory cytokines and oxylipins are restrained in
m.5019A>G macrophages. Finally, an in vivo endotoxemia model using
m.5019A>G mice reveal elevated IFN-I levels and sickness behaviour.
In conclusion, our study identifies an unexpected imbalance in innate
immune signalling in response to a pathogenic mtDNA mutation, with
important implications for the progression of pathology in patients with
mtDNA diseases. Data from this study that is included in this Dryad
submission is as follows: 1. Label-free proteomic analysis of
non-stimulated (non-stim) or lipopolysacchride (LPS)-stimulated (6 h) WT
and m.5019A>G murine bone marrow-derived macrophages (BMDMs). Five
to seven biological replicates per condition. 2. RNA sequencing of
non-stim or LPS-stimulated (1 h) WT and m.5019A>G murine bone
marrow-derived macrophages (BMDMs). Three biological replicates per
condition.