Caspase activation leads to distinct morphological changes, including mitochondrial disintegration, followed by nuclear fragmentation, chromatin condensation, and cytoplasmic membrane blebbing ( 4, 5). Apoptotic cell death is characterized by a proteolytic caspase cascade that emanates from either an ‘extrinsic’ pathway, initiated by membrane-bound death receptors leading to activation of caspase-8, or an ‘intrinsic’ pathway triggered by DNA-damaging drugs and UV radiation leading to mitochondrial depolarization and subsequent activation of caspase-9 ( 3). Regulation of apoptosis, or programmed cell death, is critical for development and tissue homeostasis, and dysregulation of apoptosis is a key factor in neoplastic transformation ( 1, 2). These studies identify PLS3 as a critical regulator of mitochondrial structure and respiration, and CL transport in apoptosis. In contrast, wild-type PLS3-transfected cells displayed increased sensitivity to apoptosis and enhanced CL translocation. The abnormal mitochondrial metabolism and structure in PLS3(F258V)-expressing cells were associated with decreased sensitivity to UV- and tBid-induced apoptosis and diminished translocation of CL to the mitochondrial outer membrane. Electron microscopic examination revealed that the mitochondria in PLS3(F258V)-expressing cells have densely packed cristae and are fewer in number and larger than those in control cells. Mitochondrial analysis revealed that PLS3(F258V)-expressing cells have decreased mitochondrial mass shown by lower cytochrome c and cardiolipin (CL) content, poor mitochondrial respiration, and reduced oxygen consumption and intracellular ATP whereas wild-type PLS3-transfected cells exhibit increased mitochondrial mass and enhanced respiration. Cells transfected with PLS3(F258V) exhibited reduced proliferative capacity. To study PLS3 function in mitochondria, we disrupted its conserved calcium-binding motif yielding an inactive mutant PLS3(F258V). Phospholipid scramblase 3 (PLS3) is a newly recognized member of a family of proteins responsible for phospholipid translocation between two lipid compartments.

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