FUNCTIONAL STUDIES OF OUTER MITOCHONDRIAL MEMBRANE PROTEINS FIS1 AND MiD51 IN MITOPHAGY AND CELL DEATH

Abstract

Adapting to a variety of physiological demands, mitochondria converge stresses and respond to maintain cellular homeostasis, fine-tuning a plethora of cellular processes. Despite little is known about the lateral organization and structure of mitochondrial outer membrane, outer mitochondrial membrane (OMM) proteins are highly emphasized in mitochondrial dynamics, coupled with continuous fission and fusion, to coordinate various mitochondria-associated processes, including autophagy and apoptosis. In this study, we focus on deciphering the functions of two OMM proteins: Fis1 and MiD51, which were originally discovered in mitochondrial fission machinery but still not well-understood for mitochondrial behaviour. In this work, we uncover the role of Fis1 in regulating mitophagy via a PINK1/Parkin-independent mechanism. In addition, we explore the “bridging” role of MiD51 in switching between apoptosis and the PINK1/Parkin-dependent mitophagy. By loss-of-function studies, we demonstrate novel roles of Fis1 and MiD51 on mitochondrial homeostasis, providing broader insights into the understanding of mitochondrial dynamics proteins.