Mitochondria sense the way forward

Bao et al. reveal how mitochondria act as sensory organelles to direct and coordinate neutrophil chemotaxis.

Neutrophils and other immune cells sensing the presence of bacterial products acquire a polarized morphology that facilitates chemotactic migration. During polarization, the serine/threonine kinase mTOR drives actin polymerization at the cell front to facilitate motility, whereas adenylyl cyclase activation at the cell rear promotes uropod formation. Purinergic receptors, which respond to ATP and its breakdown products, also become asymmetrically distributed; nucleotide-responsive P2Y2 receptors signal from the cell front while adenosine-sensitive A2a receptors accumulate at the rear. ATP produced by mitochondria is released to the cell surface, where it and its derivatives promote chemotaxis by stimulating these purinergic receptors.

Bao et al. found that mTOR signaling activates mitochondria at the front of migrating neutrophils, increasing ATP production and initiating an autocrine feedback loop downstream of P2Y2 receptors, resulting in further mitochondrial activation. Meanwhile, A2a receptor signaling blocks mitochondrial activity by inhibiting mTOR signaling at the cell rear. The bulk of the mitochondrial mass is inactivated during neutrophil chemotaxis; only a small number of mitochondria are activated, but this is sufficient to direct migrating cells.

The findings support existing models of chemotaxis that rely upon local excitatory and global inhibitory mechanisms. Senior author Wolfgang Junger now plans to investigate what happens in migrating cells when mitochondrial ATP generation is impaired, such as may occur in the hypoxic environment that accompanies sepsis.