The mitochondrial swelling channel

Early bioenergeticists who described the principles of chemiosmosis were aware that swelling of mitochondria was a likely and even frequent event, based on the large electrochemical gradient of K+ ions across the mitochondrial inner membrane. Swelling could be measured as a change in electron density by electron microscopy or by spectrophotometry in isolated mitochondria. The mitochondrial permeability transition (mPT) was originally described as an acute swelling change in mitochondria, later determined to be caused by the rapid opening of a pore (mPTP) defined biophysically and pharmacologically as a Ca2+- and voltage-dependent, cyclosporine A-sensitive large-conductance channel. The identity of the pore is controversial, but the ATP synthase c-subunit is a major candidate. In their breakthrough study (Akosah et al. https://doi.org/10.1085/jgp.202613979), they establish a novel dark-field imaging approach, allowing detection of mitochondrial swelling in living cells. Swollen mitochondria exhibit decreased light scattering and, therefore, microscopically "disappear." The cell-based imaging technique enables dissection of two separate processes, mitochondrial swelling, and depolarization. The authors demonstrate that K+ influx causes swelling but not immediate mitochondrial depolarization in wild-type cells, whereas in ATP synthase c-subunit knockout cells, Ca2+-dependent mitochondrial depolarization occurs without swelling, suggesting a lack of K+ influx. The results suggest that the ATP synthase c-subunit channel is the key member of a channel complex constituting the "swelling channel" of the mPTP.