Since PXA has antibiotic activity against organisms as diverse as bacteria, protozoans, fungi, plants and animal cells including human cancer cells, it has to affect a cellular feature that is evolutionarily highly conserved. A recent study has shown that PXA directly affects the mitochondria by disrupting both their biochemical functions and their membrane architecture. The mitochondria are cellular organelles that are present in almost all eukaryotes. According to the theory of symbiogenesis, they are derived from bacteria and share many characteristics with them, including several properties of their membrane composition.
One of the main functions of the mitochondria is to produce the cellular energy currency ATP through the process of oxidative phosphorylation (OxPhos). OxPhos depends on the mitochondrial membrane potential, which is generated by the electron transport chain (ETC) via the consumption of oxygen. PXA was shown to interfere with all of these functions of the mitochondria: not only does it decrease ATP synthesis and depolarise the mitochondria, but it also inhibits the ETC and cellular oxygen consumption. This sets it apart from uncoupling agents such as protonophores. While these also decrease ATP synthesis and depolarise the mitochondria, they increase respiration at the same time due to increased ETC activity in an attempt to restore the membrane potential.
In addition to this inhibition of the function of mitochondria, PXA also disrupts their membrane architecture. In many cell types, the mitochondria normally form an intricate tubular network that undergoes a constant process of balanced mitochondrial fission and mitochondrial fusion. Treatment with PXA or many other mitochondrial stressors, such as protonophores, causes excessive fission that results in mitochondrial fragmentation. In the case of PXA, however, this fragmentation process was shown to be different from canonical fragmentation, caused by other agents such as protonophores, in several ways: first, it is considerably faster, resulting in complete fragmentation within a minute as opposed to about 30–60 minutes for canonical fragmentation; second, it is independent from the mitochondrial fission and fusion regulators DRP1 and OPA1; and third, while PXA causes fragmentation of both the outer mitochondrial membrane (OMM) and the mitochondrial matrix in wild type cells, it causes exclusive fragmentation of the matrix in cells that lack DRP1. This last feature is especially unusual since no active mechanism for exclusive matrix fission is known in higher eukaryotes. Examination of the mitochondrial ultrastructure revealed that PXA causes cristae disruption and complete distortion of the mitochondrial matrix. It is probably through this effect that PXA induces programmed cell death in the form of apoptosis.