Mitochondrial Ca2+-signaling in inflammation and innate immunity

The innate immune system surveys peripheral tissue and provides the first line of defense against invading pathogens. Macrophages are the commanders of this innate immunity, transforming the diversity of environmental signals into functional host defense and tissue homeostasis. As we age, this chain of command breaks down. We experience a progressive loss of physiological integrity resulting in impaired immunologic functions and susceptibility to infection and disease. Within macrophage, mitochondria provide the cellular energy needed for this lifelong battle. Mitochondria are uniquely adept to rapidly respond to changes in tissue environment. The movement of Ca2+ across the mitochondrial membrane is a strike of lightning to the heart of this metabolic machine. Here we show that: (1) mitochondrial Ca2+ uptake buffers the cytosol from deviant inflammatory outputs and (2) mitochondrial Ca2+ shifts the metabolic tone of macrophages to fuel the machineries of pathogen destruction. These roles have a significant impact on aging physiology with implications for age-related diseases. In essence, the Mitochondrial Calcium Uniporter provides a spark in innate immunity previously unknown.