Sex Differences in Ischemia/Reperfusion Injury: The Role of Mitochondrial Permeability Transition

Brain and heart ischemia are among the leading causes of death and disability in both men and women, but there are significant sex differences in the incidence and severity of these diseases. Ca2+ dysregulation in response to ischemia/reperfusion injury (I/RI) is a well-recognized pathogenic mechanism leading to the death of affected cells. Excess intracellular Ca2+ causes mitochondrial matrix Ca2+ overload that can result in mitochondrial permeability transition (MPT), which can have severe consequences for mitochondrial function and trigger cell death. Recent findings indicate that estrogens and their related receptors are involved in the regulation of MPT, suggesting that sex differences in I/RI could be linked to estrogen-dependent modulation of mitochondrial Ca2+. Here, we review the evidence supporting sex differences in I/RI and the role of estrogen and estrogen receptors in producing these differences, the involvement of mitochondrial Ca2+ overload in disease pathogenesis, and the estrogen-dependent modulation of MPT that may contribute to sex differences.