From Ancient Philosophy to Endosymbiotic Theory: The Bacterial Origin and Key Role of Mitochondria in Immune Responses.

The endosymbiotic theory, which is the crucial starting point of eukaryogenesis, was first mentioned in the philosophy of the pre-Socratic Greek philosopher Empedocles. According to him, everything merges into units with differential survival. Similarly, during eukaryogenesis, the fusion of two distinct units resulted in the creation of a new cell type that possessed a newly formed organelle, the mitochondrion. Since then, the mitochondrion has been a key regulator of health and immunity. Furthermore, many of its characteristics and functions are due to its endosymbiotic bacterial origin. For example, it possesses damage-associated molecular patterns that can activate inflammatory signaling pathways, has circular DNA with CpG-rich motifs, as well as a double phospholipid membrane, and divides by fission. Mitochondrial function plays a critical role in maintaining cellular homeostasis, as they meet the cell's energy needs and regulate many of its functions. However, after cellular damage due to infection, radiation, or toxins, mitochondrial stress and dysfunction can occur and mitochondrial DNA can be released into the cytosol. Cytosolic mitochondrial DNA can then activate proinflammatory signaling pathways, mediated by TLR9 and cGAS, as well as inflammasomes, triggering inflammation and autoimmunity.