This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Mitochondria are dynamic organelles that continually undergo membrane remodeling by fission and fusion events that create and maintain the tubular structure, allowing the mitochondrial compartment to efficiently respond to metabolic needs of the cell. The proposed study focuses on understanding the mechanisms of mitochondrial fission, which appears to be an essential process in humans. During the evolution of mitochondria from prokaryotic ancestors, several primitive eukaryotic organisms, including Dictyostelium discoideum, retained the ancestral mechanism to divide their mitochondria. Our overall goal is to uncover the fission mechanism in D. discoideum and trace the evolutionary link between higher eukaryotic mitochondria and their prokaryotic ancestors. Prokaryotic cell division is mediated by FtsZ, which assembles into a ring that constricts and splits the cell into two daughter cells. Eukaryotes, such as yeast, that have apparently lost FtsZ proteins use dynamin-related proteins (DRPs) to mediate mitochondrial division. D. discoideum expresses at least two FtsZ orthologs (FszA and FszB) and appears to mediate division of its mitochondrial tubules by an FtsZ-type mechanism, possibly in conjunction with a DRP-type mechanism. A thorough understanding of eukaryotic mitochondrial fission requires knowledge of all fission mechanisms, including the rudimentary mechanisms used in D. discoideum. We hypothesize that FszA, together with its protein partners, plays a direct role in mitochondrial fission in D. discoideum by constricting and dividing the mitochondrial tubule. To test this hypothesis, we propose to develop a novel in vivo microscopy-based system to investigate fission events in D. discoideum in real time (Specific Aim 1) and to identify components of fission machinery (Specific Aim 2). Ultimately, the results of the proposed study will contribute to our understanding of mitochondrial fission, a process necessary for maintaining the tubular mitochondrial structure. Disruption of this structure has been shown to cause developmental defects, lead to neurodegenerative diseases, and affect regulation of programmed cell death. Understanding the molecular mechanisms of mitochondrial fission in eukaryotes will help us to understand the cellular process of apoptosis and develop treatments for a variety of mitochondrial diseases. Thus, understanding the processes that maintain mitochondrial structure is important to human health.
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