Mitochondria Express Functional Signaling Ligand-Binding Receptors that Regulate their Biological Responses - the Novel Role of Mitochondria as Stress-Response Sentinels.

Evidence accumulated mitochondria, as the "powerplants of the cell," express several functional receptors for external ligands that modify their function and regulate cell biology. This review sheds new light on the role of these organelles in sensing external stimuli to facilitate energy production for cellular needs. This is possible because mitochondria express some receptors on their membranes that are responsible for their autonomous responses. This is not surprising given the widely accepted hypothesis that these intracellular organelles originated from prokaryotic ancestors that fused with eukaryotic cells during early evolution. It has been reported that mitochondria express functional estrogen, androgen, glucocorticoid, 5-hydroxytryptamine, melatonin, and cannabinoid receptors. What is intriguing is recent evidence showing that mitochondria could also be directly regulated by active mediators of intracellular complement (complosome) and intrinsic mediators of purinergic signaling. Accordingly, they express receptors for intracellular complement cleavage fragments (C5a and C3a) as well as for adenosine triphosphate (ATP), which, besides its crucial role in transferring energy in the cells, is also an important signaling molecule interacting with P2X7 receptor expressed not only on the cell surface but also on the mitochondria membrane. Based on this, intrinsic complosome and purinergic signaling mediators emerge as important cooperating regulators of reactive oxygen species (ROS) release from mitochondria and activators of intracellular pattern recognition receptor Nlrp3 inflammasome. This activation within the beneficial "hormetic zone response" regulates cell metabolism, proliferation, migration, and adaptation to the surrounding challenges of the microenvironment in a favorable way.