The NDUFA4 family of mitochondrial proteins – key regulators of inflammation?

Mitochondria are central regulators of immune cell function during health and disease. The little-studied gene C15orf48 is conserved across 450 million years of evolution, and was recently identified as a member of the NDUFA4 family of mitochondrial electron transport chain subunits. This gene produces a protein that replaces the NDUFA4 subunit within mitochondrial complex IV in activated myeloid cells, and is amongst the most highly upregulated genes in many inflammation-associated diseases. Macrophages lacking NDUFA4 are hyper-inflammatory, however the mechanisms driving this are unknown, and the implications of NDUFA4/C15orf48 exchange for mitochondrial biology, immune cell functionality and inflammatory disease are poorly understood. I will interrogate how regulation of this protein family and mitochondrial electron transport chain organisation controls inflammatory processes. Using knock-out mouse models, primary human macrophages, induced pluripotent stem cells and patient samples, I will determine the molecular functions of the NDUFA4 family and their roles in macrophage metabolism and activity. Using models of lung inflammation and sepsis, I will uncover the role of C15orf48 in local and systemic inflammatory responses in vivo. This work will bring crucial insight into fundamental processes of mitochondrial biology and immunometabolism, shifting our understanding of how mitochondrial regulation governs immune function and inflammatory disease.