Mitochondrial sensitivity to Ca²⁺-induced permeability transition in mouse liver exhibits time-of-day dependence

Mitochondrial permeability transition (MPT) is a loss of mitochondrial inner membrane integrity following opening of the MPT pore in the mitochondrial inner membrane that can lead to cell death. Whether hepatic MPT sensitivity fluctuates across the day remains unclear. Here, we examined time-of-day regulation of mitochondrial sensitivity to MPT in mouse liver. We found that MPT sensitivity of hepatic mitochondria fluctuates across the day with a peak near the end of the light (inactive) phase and a trough near the end of the dark (active) phase. Restricting the feeding time window to the active or inactive phase shifted the phase of this rhythm, indicating that feeding rhythm strongly contributes to the fluctuation of MPT sensitivity. This fluctuation in MPT sensitivity was inversely correlated with mitochondrial glutathione levels. To examine the involvement of the circadian clock in these fluctuations, we compared these fluctuations between hepatocyte-specific Bmal1 knockout mice (Bmal1-LKO) and their littermates. In Bmal1-LKO, the circadian fluctuation of MPT sensitivity and mitochondrial glutathione levels were attenuated. Moreover, time-of-day differences in ischemia/reperfusion-associated MPT and liver injury were altered in Bmal1-LKO. Collectively, these findings suggest that feeding rhythms and hepatocyte Bmal1 are involved in shaping time-of-day-dependent MPT sensitivity, in part through oscillation of the mitochondrial glutathione pool, thereby influencing early susceptibility to ischemia/reperfusion injury. These findings demonstrate that mitochondrial sensitivity to MPT represents a temporally regulated toxicological threshold in the liver, which may influence early vulnerability to hepatic injury.