Alternative Targets for Modulators of Mitochondrial Potassium Channels

Abstract

Mitochondrial potassium channels control potassium influx into the mitochondrial matrix and thus regulate mitochondrial membrane potential, volume, respiration, and synthesis of reactive oxygen species (ROS). It has been found that pharmacological activation of mitochondrial potassium channels during ischemia/reperfusion (I/R) injury activates cytoprotective mechanisms resulting in increased cell survival. In cancer cells, the inhibition of these channels leads to increased cell death. Therefore, mitochondrial potassium channels are intriguing targets for the development of new pharmacological strategies. In most cases, however, the substances that modulate the mitochondrial potassium channels have a few alternative targets in the cell. This may result in unexpected or unwanted effects induced by these compounds. In our review, we briefly present the various classes of mitochondrial potassium (mitoK) channels and describe the chemical compounds that modulate their activity. We also describe examples of the multidirectional activity of the activators and inhibitors of mitochondrial potassium channels.

Current Challenges of Mitochondrial Potassium Channel Research

“…Few voltage-gated potassium channels, including mitoKv1.3, mitoKv1.5, and mitoKv7.4, have been identified in mitochondria. These channels are similar to those found in the plasma membrane of various cells ( Szabo et al, 2005 ; Checchetto et al, 2018 ; Wrzosek et al, 2022 ). The pore-forming α subunit of the Kv1.3 channel contains voltage-sensing domains and is encoded by the KCNA3 gene.…”

“…Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are localized mainly in the plasma membrane, although they have also been detected in the mitochondria. This was suggested for rat kidneys, human HEK 293 cells, and human cardiac tissue ( Leon-Aparicio et al, 2019 ; Wrzosek et al, 2022 ). We believe that their presence in mitochondrial membranes and molecular origin need further confirmation.…”

“…The mammalian TASK-3 channel encoded by KCNK9 gene has been identified in the inner mitochondrial membrane of melanocytes, melanomas (WM35 and B16F10), and keratinocytes. In the human keratinocyte HaCaT cell line the mitochondrial TASK-3 had a conductance of 83 pS at positive voltages and 12 pS at negative voltages in symmetric 150 mM KCl, as measured by the single-channel patch clamp technique ( Nagy et al, 2014 ; Toczylowska-Maminska et al, 2014 ; Wrzosek et al, 2022 ).…”

“…However, experiments characterizing the role of mitochondrial potassium channels in isolated mitochondria or in intact cells revealed that pharmacological tools have serious limitations. Unfortunately, the majority of mitochondrial potassium channel modulators exhibit a wide range of off-target effects ( Szabo et al, 2021 ; Wrzosek et al, 2022 ). Mitochondria seem to be especially susceptible to the nonspecific action of channel modulators.…”

“…Due to the similar structure of potassium channels, some of these compounds interact with the channels found in the inner mitochondrial membrane. As mentioned above, a number of plasma membrane modulators, potassium channel openers, and inhibitors have been tested, and some have also been shown to regulate potassium channels that are located in the inner mitochondrial membrane ( Leanza et al, 2019 ; Wrzosek et al, 2020 ; Wrzosek et al, 2022 ).…”