Current Challenges and Future Directions in Mitochondrial Potassium Transport Research

Maintenance of ionic homeostasis, particularly the balance of potassium ions as the major cations in the cytoplasm, is critically important for mitochondrial function. Uncontrolled cation influx and the subsequent osmotically-driven water accumulation in the matrix could lead to swelling and eventual membrane rupture. Paradoxically, despite the critical importance of potassium channels and exchangers and their extensive research history, molecular identity of the key potassium transport systems such as the K⁺/H⁺ exchanger and the ATP-dependent potassium channel remains a subject of ongoing debate. Within this review and analysis of scientific publications, we outline a number of unresolved issues related to potassium transport in mitochondria: incomplete knowledge of structural and functional rearrangements in mitochondria upon potassium ion influx and swelling; ambiguity surrounding molecular identity of the key potassium transport systems - the K⁺/H⁺ exchanger and the ATP-dependent potassium channel, as well as uncertain role of ATP synthase in ion transport; and the apparent underestimation of the role of the lipid component of the membrane in direct potassium transport and its regulation. We highlight that accumulation of lysocardiolipin, a derivative of the key mitochondrial lipid cardiolipin, in the membrane may represent a missing link crucial for constructing a comprehensive explanation of mitochondrial osmotic regulation mechanisms. Lysocardiolipin can form lipid pores that significantly enhance membrane conductance for cations. Accumulation of lysocardiolipin could be stimulated by lipid peroxidation, could alter membrane properties, and modulate assembly and function of the proteinaceous ion transporters. Accounting for the changes in physical (pressure, lipid packing) and chemical properties of the membrane (peroxidation, deacylation) during conditions that activate osmotic regulation systems is necessary for forming a holistic understanding of potassium transport mechanisms.