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Mitochondria as usEP Sensors

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Ultrashort Electric Pulse Effects in Biology and Medicine

Part of the book series: Series in BioEngineering ((SERBIOENG))

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Abstract

The endocytotic and symbiotic inclusion of a prokaryote by an early eukaryote, its subsequent evolution as mitochondria, and its collaboration with the nucleus provided these new symbiotes with enough ATP to evolve a new world of extraordinarily diverse organisms. Mitochondria assumed roles for lives replete with energy from ATP and control over the death of cells when their usefulness was finished or when they malfunctioned or were injured beyond repair. The outer mitochondrial membrane (OMM) protects the electron transport chain (ETC) in the inner mitochondrial membrane and the mitochondria’s DNA, which is used for some of the proteins in the ETC. The ETC is supplied with electrons from NADH, FADH2 produced by oxidative phosphorylation (OXPHOS) as Complexes I, III, and IV pump proton (H +) out of the matrix to generate a proton motive force and a mitochondrial membrane potential (ΔΨm). H + reenter the matrix through ATP synthase for the production of ATP. All this complexity provides usEPs with multiple targets for effects on cell life and death. UsEP’s role in cytochrome c release in apoptosis and other regulated cell death (RCD) mechanisms in cancer ablation has been a significant application with clinical medicine, which is still in developmental stages in clinical trials. UsEPs increase reactive oxygen species (ROS) and dissipate the ΔΨm, which can occur without permeabilization of the IMM, especially in the presence of Ca2+ that enters cells through nanopores in the plasma membrane. This loss of ΔΨm is facilitated by usEP effects on the Ca2+-dependent and redox-sensitive protein cyclophilin D (CypD). CypD regulates the mitochondrial permeability transition pore (mPTP) that dissipates the ΔΨm, leading to regulated cell death and apoptosis if mitochondria release cytochrome c into the cytoplasm to activate caspases. We also discuss the possible identity of the mPTP as ATP synthase. Experiments continue to test this hypothesis. Experiments here also show that usEPs with a shorter (faster) rise-fall time are more effective to dissipate ΔΨm than usEPs with a longer (slower) rise-fall time. It also appears that over-expression of BCL-xl and BCL2 cannot protect the mitochondria from the effects of usEPs. Experiments measuring oxygen consumption in cells treated or not with usEPs indicate that the usEPs attenuate oxygen consumption in Complexes I and IV of the ETC. These results suggest that usEPs inhibit electron transport in the ETC. We also show that usEPs that ultimately lead to cell death in 4T1-luc mammary cancer cells up-regulates essential subunits in the ETC. Thus, usEPs target several mitochondrial components, including those that regulate ΔΨm and electron transport in the ETC.

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  1. Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, USA

    Stephen J. Beebe

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Beebe, S.J. (2021). Mitochondria as usEP Sensors. In: Ultrashort Electric Pulse Effects in Biology and Medicine. Series in BioEngineering. Springer, Singapore. https://doi.org/10.1007/978-981-10-5113-5_8

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