The molecular mechanism of opening the mitochondrial permeability transition pore (mPTP) remains a mystery. Additionally, the molecular identity of the mPTP is a topic of much debate. The ATP synthase c-subunit ring has recently been reported to play a key role in the formation of the mPTP, and has been found to form a voltage-sensistive channel that is similar to the behavior of the mPTP channel. The main point of controversy is the hydrophobic nature of the c-subunit pore, dismissing this idea previously. However, we have found that in the bovine ATP synthase c-subunit ring, there are many hydrophilic residues in the pore that allow for a partial water leak channel to form, when voltage is applied. Between the voltages of -30 and -180 mV, we observe water permeating through the c-subunit pore, with the amount of water increasing as voltage increases. Gradually increasing voltage causes the c-subunit ring to undergo conformational changes, expanding its size. Performing mutations that loosen the packing of the ring have shown to further increase the diameter and conductance of the ring, as well as water permeation. Finally, a full water channel is able to be formed once deprotonation occurs on key acidic residues in the center of the c-subunit ring. Essentially, we explore a mechanism of a voltage-sensitive ATP synthase c-subunit ring that exhibits similar behavior to the mPTP channel, supportive of this c-subunit playing a key role in mPTP formation.

Curious case of a leaky mitochondria

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ACS Fall 2022

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