Once thought to be static, bean-shaped organelles, mitochondria are now recognized as highly dynamic structures that continuously undergo fission and fusion. While balancing fission and fusion maintains overall organelle homeostasis, cellular stress can tip this equilibrium, selectively hyperactivating one of these opposing processes. Decades of elegant fluorescence microscopy and biochemical experiments have highlighted the spatiotemporal dynamics and protein players involved in these mitochondrial remodeling pathways. However, what remains hidden are the intricate molecular structure of these players—their assembly, spatial organization, and conformations—that enable dynamic functional organellar remodeling. We propose that unveiling these structural intricacies will yield profound insights into previously unimaginable levels of mitochondrial regulation that can be therapeutically targeted to mitigate mitochondrial dysfunction implicated in many human diseases, such as neurodegeneration and cancer.
Our lab combines recent advances in cellular cryo-electron tomography (cryo-ET) and super-resolution fluorescence microscopy to define the structural and functional interactions that regulate mitochondrial behavior under stress and changing cellular demands. Through our innovative “structure-mapping” pipeline, we investigate the molecular mechanisms underlying (1) mitochondrial division (fission), (2) the mitochondrial stress response, and (3) mitochondrial protein import.
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