Sundborger-Lunna lab
We use a combination of molecular biology, biochemical and biophysical techniques, including cryo-electron microscopy, to study how membrane-remodeling proteins regulate critical cell death processes. Our goal is to understand the interplay between membrane remodeling proteins and membrane lipids to regulate cell fate.
Popular science presentation
Mitochondria are intracellular organelles that are essential for many cellular functions that regulate cell survival and cell death. Thus, dysregulation of mitochondria may lead to cell death and disease. Death of neurons (neurodegeneration) contributes to the development of devastating ailments, such as Huntington’s disease, a hereditary progressively deteriorating condition characterized by uncoordinated and involuntary movement and dementia, with no known cure.
Mitochondrial function is maintained by dynamic fission and fusion events, opposing processes of mitochondria dividing (fission) and joining together into larger structures (fusion). This constant cycle is controlled by various different proteins that specifically bind to mitochondrial membranes to modify their shapes. Exactly how these proteins control mitochondrial behaviour is not fully understood. Our lab studies how these proteins interact with mitochondrial membranes to promote fission and fusion using a variety of various methods, including cryo-electron microscopy. Cryo-electron microscopy has the power to reveal very detailed information of molecules, like proteins or protein-lipid complexes. We use this technique and others to reveal in great detail the organization of proteins that modulate mitochondrial membrane shape to increase our understanding of cellular events that lead to neuronal cell death or survival. Our goal is to describe novel cellular mechanisms and to identify potential molecular targets for drug development and prevention of catastrophic neurodegenerative diseases like Huntington’s disease.
Research projects
Mitochondrial function and quality control depend on dynamic remodeling of the outer mitochondrial membrane (OMM). These remodeling events determine whether damaged mitochondria are eliminated through mitophagy or whether mitochondrial permeabilization triggers apoptosis. Dysregulation of these processes is a hallmark of multiple diseases, including cancer and neurodegeneration. Our research focuses on understanding how protein assemblies and lipid organization coordinate mitochondrial membrane remodeling to control cell fate decisions. A central theme of our work is that membrane remodeling is governed by higher-order protein–lipid assemblies that organize mitochondrial membranes. We investigate how these assemblies integrate membrane curvature, lipid composition, and protein oligomerization to regulate mitochondrial quality control and apoptotic signaling. Our current research addresses three closely related questions:
1. How are mitochondrial membrane remodeling hubs organized to control the decision between mitophagy and apoptosis?
Cardiolipin (CL), a mitochondria-specific phospholipid, redistributes to the outer mitochondrial membrane during cellular stress and promotes membrane curvature and packing defects. We investigate how the mitochondrial BAR-domain protein endophilin B1 (EnB1) senses and remodels CL-containing membranes. Our work indicates that EnB1 can assemble into distinct higher-order states on mitochondrial membranes and can also form biomolecular condensates that organize lipid–protein remodeling hubs. These assemblies appear to generate different membrane outcomes: scaffold-like assemblies promote membrane tubulation associated with mitochondrial quality control pathways, whereas alternative assemblies destabilize the membrane and facilitate apoptotic membrane remodeling. Understanding how these assemblies form and are regulated is central to explaining how mitochondrial remodeling governs cellular fate.
2. How do mitochondrial remodeling proteins cooperate with apoptotic machinery to regulate mitochondrial permeabilization?
Activation of the Bcl-2 family protein Bax is a key step in mitochondrial apoptosis. Our work indicates that EnB1 directly interacts with Bax and promotes its recruitment and assembly on cardiolipin-containing membranes. We investigate how this interaction influences Bax oligomerization and pore formation at the mitochondrial outer membrane, and how lipid composition and membrane curvature modulate this process. These studies aim to establish how mitochondrial membrane remodeling proteins function upstream of apoptotic pore formation and how dysregulation of these mechanisms contributes to diseases such as aggressive cancers.
3. How does amyloid protein misfolding influence mitochondrial membrane remodeling and cell death pathways in neurodegeneration?
Mutant Huntingtin (mtHtt), the causative protein in Huntington’s disease, is known to interact with membrane remodeling proteins including dynamin and endophilins. Htt also exhibits anti-apoptotic properties and has been implicated in mitochondrial dysfunction observed in Huntington’s disease. We investigate whether misfolded or aggregated Htt perturbs the mitochondrial remodeling mechanisms described in Questions 1 and 2. Specifically, we test whether Htt alters the assembly or activity of EnB1 at mitochondrial membranes, affects cardiolipin organization, or modulates Bax recruitment and activation. By linking amyloid misfolding to mitochondrial membrane remodeling, these studies aim to explain how protein aggregation may disrupt mitochondrial quality control and trigger neuronal cell death.
To address these questions, we combine biochemical reconstitution, protein–lipid interaction assays, cell biology, and advanced structural approaches including cryo-electron microscopy and cryo-electron tomography. Our goal is to uncover the molecular principles by which protein assemblies and lipid organization coordinate mitochondrial membrane remodeling and thereby regulate fundamental cell death–survival decisions. In the long term, this work aims to identify mechanistic targets for therapeutic strategies aimed at restoring mitochondrial homeostasis in diseases such as cancer and neurodegeneration.
Selected publications
Peripheral membrane protein endophilin B1 probes, perturbs and permeabilizes lipid bilayers, Thorlacius, et al, 2025, Communications Biology
Amphipathic Motifs Regulate N-BAR Protein Endophilin B1 Auto-inhibition and Drive Membrane Remodeling, Bhatt, et al, 2021, STRUCTURE
Funding
