Mitochondrial K+ Transport: Modulation and Functional Consequences

Abstract

The existence of a K+ cycle in mitochondria has been predicted since the development of the chemiosmotic theory and has been shown to be crucial for several cellular phenomena, including regulation of mitochondrial volume and redox state. One of the pathways known to participate in K+ cycling is the ATP-sensitive K+ channel, MitoKATP. This channel was vastly studied for promoting protection against ischemia reperfusion when pharmacologically activated, although its molecular identity remained unknown for decades. The recent molecular characterization of MitoKATP has opened new possibilities for modulation of this channel as a mechanism to control cellular processes. Here, we discuss different strategies to control MitoKATP activity and consider how these could be used as tools to regulate metabolism and cellular events.

Alternative Targets for Modulators of Mitochondrial Potassium Channels

“…The list of pharmacological modulators of the mitoK ATP channel is relatively long. Diazoxide and BMS191095 can be treated as canonical pharmacological activators of the mitoK ATP channel [ 25 ], along with nicorandil, cromakalim, pinacidil, or P1075. Inhibitors of the mitoK ATP channel include glibenclamide (glyburide), 5-hydroxydecanoic acid (5-HD), tetraphenylphosphonium, and 4-aminopyridine [ 1 , 25 ].…”

“…Diazoxide and BMS191095 can be treated as canonical pharmacological activators of the mitoK ATP channel [ 25 ], along with nicorandil, cromakalim, pinacidil, or P1075. Inhibitors of the mitoK ATP channel include glibenclamide (glyburide), 5-hydroxydecanoic acid (5-HD), tetraphenylphosphonium, and 4-aminopyridine [ 1 , 25 ]. 5-HD is described as a relatively selective inhibitor of mitoK ATP channels, and it does not inhibit plasma membrane K ATP channels [ 6 , 23 ].…”

Prescription drugs and mitochondrial metabolism

“…However, there does not appear to be any direct evidence that glyburide alters mitochondrial metabolism in intact β-cells, and a mouse β-cell line depleted of mitochondrial DNA remained sensitive to glyburide-stimulated insulin secretion [ 133 ]. However, mitochondrial effects in other tissues have been of interest due to apparent cardio and renal toxicity of this drug, as well as compounding evidence regarding the function of mitochondrial K ATP channel activities (reviewed by Pereira and Kowaltowski [ 134 ]). In humans, glyburide accumulates in highly perfused organs such as liver and kidney [ 135 ].…”

Routes for Potassium Ions across Mitochondrial Membranes: A Biophysical Point of View with Special Focus on the ATP-Sensitive K+ Channel

“…This finding, along with the pharmacological profile mentioned above, prompted the researchers to propose the Kir6.2 inward rectifying channel as the main pore-forming constituent of mitoKATP. Despite the fact that the molecular composition of mitoKATP was not elucidated, the field of mitoKATP channel underwent a rapid evolution when pharmacological studies highlighted an important role of this channel in cardioprotection, in particular in attenuating the damage caused by ischemia-reperfusion (for recent reviews see, e.g., [6,7,13]. Moreover, mitoKATP activation has been proposed to exert neuroprotective effects [106] and to modulate mitochondrial dynamics, biogenesis and neurodegenerative disorders such as Parkinson [107].…”

“…Despite this assumption, the author predicted the necessity for ions to be transported through the IMM. Indeed, extensive research over the last few decades has highlighted an important role for potassium transporters/channels in the regulation of the IMM potential (∆ψ), redox state and mitochondrial volume, as summarized by recent, detailed reviews, e.g., [2][3][4][5][6][7]. By modulating these important factors, K + channels impact not only on bioenergetic efficiency and ATP production by mitochondria, but also on cellular signaling events such as, for example, apoptotic signaling [8,9], Wnt signaling [10], and cGMP-related pathways [11].…”