Lysosomal Membrane -Rupture (LMR) and -Permeabilization (LMP) are Distinct for Cell Death

Lysosome is crucial for maintaining cellular homeostasis, but disintegrity of its limiting membrane affects the cell death fate. From 1972 to 1999, via the cytochemistry of cultured cells which were exposed to stresses, Brunk et al. defined lysosomal membrane permeabilization (LMP) as leakage through the ultrastructurally-intact limiting membrane. In 1996, via the electron microscopic analysis of the monkey hippocampal CA1 neurons after transient ischemia, Yamashima et al. identified lysosomal membrane rupture (LMR) as an apparent disruption of the limiting membrane. To elucidate the mechanism of lysosomal cell death, it is indispensable to precisely differentiate LMP and its extensive form LMR. LMP indicates formation of ultrastructurally-undetectable, tiny pores at the lysosomal limiting membrane that allow selective leakage of lysosomal contents. LMP contributes to amplification of the cell death signal, and participates in apoptosis. If only a small number of lysosomes is affected, the cell can eliminate injured lysosomes via activating lysophagy, and ensure cell survival. However, when majority of lysosomes are affected, the cell develops apoptosis. In contrast, LMR indicates presence of larger holes that cause acute and massive leakage of hydrolytic cathepsin enzymes. LMR leads to the rapid and explosive vanishment of lysosomes, which results in necrosis. Each form of cell death is carried out, depending upon the size and number of perforations, the amount of leakage, and the cellular context. The modality of the lysosomal membrane disintegrity, i.e., LMP or LMR, determines cell death fate. It is likely that apoptosis occurs by the proteolytic activation of caspases via LMP, whereas necrosis occurs by the calpain-cathepsin cascade via LMR. This paper is to review ultrastructural evidences of LMR which were identified in diverse pathologic conditions of C. elegans, mice, monkeys, and humans. For elucidating mechanisms of each cell death at stresses or diseases, LMP and LMR should be precisely differentiated by electron microscopy.