Poster - #UCLA-61 - Keywords: mitochondria mitochondrial dynamics SLC25A46 metabolism fission fusion

A Role for SLC25A46 in Mediating Mitochondrial Dynamics

Sean Atamdede, Jordan Tibbs, Janos Steffen, David Austin, Ryan Howe, Merin Rixen, Eileen Olivares, Alex van der Bliek, Robert Damoiseaux, and Carla Koehler
University of California-Los Angeles (UCLA)

ABSTRACT:
Mediation of mitochondrial dynamics is essential to the health of an organism and its cells. If this process is disrupted, several diseases can result, including Pontocerebellar Hypoplasia (PCH), Charcot-Marie-Tooth Disease Type 2 (CMT2), and Optic Atrophy. Maintenance of a healthy mitochondrial network relies on a delicate balance between mitochondrial fission and fusion. The two processes must be coordinated across the inner and outer mitochondrial membranes, but how this occurs is not very well understood. Recently, we have identified a protein, SLC25A46, that may be responsible for coordinating the two processes. The protein is a member of the Solute Carrier Family but is localized to the outer mitochondrial membrane unlike the other solute carrier proteins, which are localized to the inner mitochondrial membrane. The protein has been shown to interact with several proteins including fusion regulators Mitofusin 1+2 (MFN1+2) on the outer membrane and Dynamin-like 120kDa Protein (OPA1) on the inner membrane along with Mitochondrial Fission Factor (MFF) and several members of the Mitochondrial Cristae Organizing System (MiCOS) complex. When expression of SLC25A46 is downregulated, expression of MFN1+2 is increased and a hyperfused mitochondrial network is observed. The same phenotype results when the gene encoding the protein undergoes a point mutation at Position 341 from leucine to proline (L341P). The misfolded protein is properly imported into the mitochondria, but is promptly degraded by the ubiquitin-proteasome system (UPS). This process occurs independently of mitophagy, making SLC25A46 L341P a model substrate to study the process of Outer Mitochondrial Membrane Associated Degradation (OMMAD.) It has recently been suggested that SLC25A46 may have a competing role with Mitochondrial Carrier Homolog 2 (MTCH2 aka SLC25A50), as MTCH2 downregulation results in a fragmented mitochondrial network and has higher expression when SLC25A46 undergoes a L341P mutation. MTCH2 also has a known role in regulating lipid metabolism, so we look to find whether SLC25A46 has a similar competing function as well. Both proteins belong to the solute carrier family and are found on the mitochondrial outer membrane yet have no known transporter function. This project looks to determine the role of SLC25A46 in mediating mitochondrial processes and how deficiencies in its function can result in disease states.