Spatial organization and dynamics of cellular systems
Human cells are enclosed by a plasma membrane. Inside the plasma membrane, there are many other membranes, which define the external boundary and the spatial identity of intracellular compartments, or organelles. Cells sequester critical biochemical reactions into these discrete membranous compartments, whereby membrane-associated processes driven by protein catalysts facilitate differentiation, communication, and spatial organization of intracellular compartments. Many organelles have very distinct shapes and subcellular localizations, but they are also dynamic, and they interact with each other. The proper morphology and spatial distribution of organelles are important for many key cellular processes including signaling, polarization, and development.
The goal of the Aydin lab is to understand how organelles adapt their morphology and spatial distribution to changing cellular conditions and how proteins and protein complexes that are associated with membranes regulate the structure and function of the organelles in cells. Building on our experience in cellular structural biology and interest in biomolecular machines, we aim to develop a molecular understanding of human cellular dynamics.
Molecular mechanisms of mitochondrial form, function and movement
Mitochondria are essential eukaryotic organelles that are involved in numerous key cellular functions, including energy production, metabolism, signaling, and regulated cell death. Mitochondria are double-membrane bound organelles that consist of four major compartments: the outer membrane (OM), intermembrane space (IMS), inner membrane (IM), and matrix. IM interacts with the OM at contact sites and folds inward to form cristae. Often visualized as “rugby balls” in textbooks, the mitochondrial reticulum is in fact highly dynamic and frequently fuses and divides to adopt divergent morphologies in different tissues. This morphological plasticity is critical for adapting to energy demands and preserving homeostasis. Our research interests are largely directed towards elucidating the molecular mechanism of regulated mitochondrial morphology for developing a molecular understanding of mitochondrial function in human cells.
We are particularly interested in learning how mitochondrial protein networks communicate cellular signals to regulate mitochondrial morphology and function, and how perturbations of this interplay underlie the development and progression of the disease. We utilize a multi-disciplinary approach that integrates structure determination by electron cryo-microscopy (cryoEM) with biochemistry, biophysics, and cell biology tools to derive unique insights into the complexity of mitochondrial dynamics. Our long-term goal is to understand how mutations and dysregulation of mitochondrial protein machines are linked to human disease and age-related illness. An integrative understanding of how mitochondrial protein networks function has implications for targeting a wide range of neurodegenerative diseases, cancers, metabolic disorders, cardiac dysfunction, and aging.
Insights into the molecular drivers of cell-cell fusion
Although no universal mechanism may exist, characterization of major cellular fusion processes unifies the concepts and provides a better understanding of precise structural and functional signatures essential for cell-cell recognition, adhesion, and fusion.
To achieve this, we aim to develop a biochemical framework that enable direct visualization fusion machineries and complement this with cellular imaging techniques to investigate interactions enabling the vastly large remodeling of cellular landscape. These approaches will provide structural and functional insights into the molecular mechanisms of cell fusion in the regulation of spatial organization human cells and are of direct relevance to engineering spatial organization of dynamic processes in cellular and cell-free systems.
Membrane fusion is an essential process in cell biology, whereby two separate lipid bilayers come in close contact with one another and merge into a single membrane. Membrane fusion can occur between cells and between intracellular compartments to facilitate various cellular processes throughout mammalian fertilization, placentation, organ shaping, muscle development, immune response, tissue regeneration, intracellular communication, and carcinogenesis. The fusion reaction between two lipid bilayers is generally mediated by specific fusion proteins that can locally disturb the lipid bilayers. The kinetic energy barriers related to membrane deformations are very high, and membrane fusion-mediating proteins are required to overcome these energy barriers and catalyze the merger of the two lipid bilayers. However, divergent mechanisms of cell membrane fusion raise challenges for characterizing their regulation and complex triggering mechanisms.