Thursday, May 9, 2024
5/9/2024
Project Summary Mitochondria are most popularly known as the powerhouse of the cell due to their role in ATP production. However, new and emerging roles for the mitochondria are continuously being discovered, providing new avenues for investigating various diseases. One of these aspects is understanding how mitochondria morphology contributes to mitochondria function. Neurodegenerative diseases, metabolic disorders, and heart failure all have evidence of mitochondria dysfunction with evidence of abnormal mitochondria morphology. Knowledge of how mitochondria morphology is regulated could provide a new spotlight on new potential drug targets that could help alleviate a broad spectrum of diseases. A series of GTPases regulate the fusion and division of the inner and outer mitochondria membranes. Optic Atrophy 1 (OPA1) is the GTPase responsible for the fusion of the mitochondrial inner membrane. There are many isoforms of OPA1 which are categorized as the active long-form OPA1 which can be proteolytically cleaved to produce inactive short-form OPA1. Interestingly, depletion of a mitochondrial chaperonin, Heat Shock Protein Family E Member 1 (HSPE1), promotes the cleavage of OPA1 into the inactive short-from. Mitochondrial chaperonin facilitates proper protein folding within the mitochondria since most proteins are translated outside the mitochondria and imported through the inner and outer membranes. To maintain mitochondrial proteostasis, HSPE1 functions with co- chaperonin, Heat Shock Protein Family D Member 1 (HSPD1). However, only depletion of HSPE1 leads to cleavage of OPA1, indicating HSPE1 could have new and exciting functions beyond its canonical role as a chaperonin. Thus, the main goal of this project is to investigate how regulation of mitochondria proteostasis could impact mitochondria dynamics through the following specific aims. Aim 1 looks to identify the interactors of HSPE1 and HSPD1 using proximity labeling combined with mass spectrometry. Subsequent depletion of these interactors using RNAi is expected to influence OPA1 cleavage. Aim 2 will investigate the role of long- form OPA1 compared to short-form OPA1. Aside from favoring mitochondria division, there is no clear census on the function of these short-form OPA1. Aim 2 proposes to overexpress short-form OPA1 to see whether there are changes to mitochondrial morphology, ATP production, and mitochondrial DNA localization. Similarly, Overexpression of uncleavable long-form OPA1 will assess whether the mitochondria dysfunction caused by HSPE1 depletion can be rescued. These specific aims are crucial in understanding how changes in mitochondria proteostasis can affect mitochondria dynamics and vice versa.
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