| Apoptosis is a genetically-programmed form of cell death that is critical for proper development, tissue homeostasis, and immune function in vertebrate organisms. Disrupted regulation of this process contributes to diverse diseases such as cancer, neurodegenerative disorders, and autoimmune dysfunction. Our knowledge of apoptosis is incomplete, especially the mechanisms governing MOMP (mitochondrial outer membrane permeabilization)--a critical control point during which cytochrome c and other mitochondrial intermembrane space proteins are released, triggering the execution of apoptosis. Our understanding of this process can be enhanced by identifying proteins involved in its regulation. In this work, two proteins—MAGE-D2 (melanoma antigen family D2) and SUMI-1 (survival-promoting mitochondrial protein 1, also known as CHCHD2 for coiled coil-helix-coiled-coil-helix-domain containing 2)—are identified as novel potential regulators of apoptosis. Initially, these proteins were identified in a screen for novel interacting partners of the pro-apoptotic protein p32/C1QBP (complement component 1, q subcomponent binding protein). This screen was undertaken in an effort to better understand the mechanisms by which p32 regulates apoptosis; however, in this work, the functions of MAGE-D2 and SUMI-1 are characterized separately from p32. Here, we show that MAGE-D2 is localized to the nucleolus, nucleus, and possibly the mitochondria, and preliminary data suggest potential roles for MAGE-D2 in apoptosis and cell cycle control. SUMI-1 is characterized more extensively in this work, and the data presented here establish SUMI-1 as a novel mitochondria-localized regulator of mitochondrial fission-fusion dynamics and BAX-mediated apoptosis. The data shown here support a model in which SUMI-1 resides at the mitochondrial outer membrane, where it regulates mitochondrial fusion and protects cells from apoptosis. Upon treatment with apoptosis-inducing stimuli, SUMI-1 translocates from the mitochondria, inhibiting mitochondrial fusion while fission continues unperturbed. This imbalance results in mitochondrial fragmentation, promoting BAX oligomerization on the mitochondrial outer membrane and ultimately leading to MOMP, cytochrome c release, and apoptosis. This body of work provides a subcellular localization and functional data for two previously uncharacterized proteins and contributes to our understanding of the signaling pathways regulating apoptosis. These data, as well as discussion of the results and future directions, are described herein. |
