BPS2026 – Mitochondrial resilience mechanisms in Drosophila melanogaster: Structure-function studies of ATP synthase

Mitochondria are complex organelles that regulate cellular metabolism and cell death. In response to Ca 2+ and reactive oxygen species overload, they undergo mitochondrial permeability transition (mPT), caused by the opening of the mitochondrial permeability transition pore (mPTP). The mPTP is a non-selective 1.5 kDa channel that forms within the otherwise impermeable inner mitochondrial membrane. Under prolonged opening of the mPTP, mitochondria undergo an osmotic imbalance, leading to swelling and subsequent rupture of the outer membrane, followed by the release of apoptotic factors and cell death. Although the mPTP is crucial in regulating cell death, its identity, structure, and gating mechanism are poorly understood. To add to the complexity, different species of the animal kingdom have evolved to possess diverse properties of mitochondrial permeability transition. Species such as the brine shrimp, Artemia franciscana , and the fruit fly, Drosophila melanogaster , are resistant to Ca 2+ -induced mPT and mitochondrial swelling. Mitochondrial ATP synthase has been recently discovered to possess a channel within its c-ring with similar biophysical characteristics of the mPTP, such as conductance, probability of channel opening, and sensitivity to Ca 2+ . Therefore, using comparative structural and functional analysis of ATP synthase across species may help in understanding the gating mechanism and molecular identity of this channel. Using cryo-electron microscopy and electrophysiology experiments, we are investigating the gating mechanism of the ATP synthase leak channel (ACLC) in D. melanogaster and mammals. Our studies revealed the molecular elements within the D. melanogaster ATP synthase that may contribute to channel inhibition and the lack of mPTP in this organism.