BPS2026 – The role of lipid composition on Drp1 variable domain conformation

Mitochondria are essential organelles responsible for producing cellular energy in the form of adenosine triphosphate. Their function depends on a dynamic balance between fusion and fission, processes that continuously remodel the mitochondrial network. Understanding the mechanisms that regulate these processes is therefore of critical importance. This study focuses on dynamin-related protein 1 (Drp1), a GTPase that mediates mitochondrial fission. Like other dynamin family proteins, Drp1 oligomerizes into ring-like structures around mitochondria, and GTP hydrolysis drives ring constriction. Under mitochondrial stress, cardiolipin (CL, a lipid enriched in the inner mitochondrial membrane) is translocated to the outer mitochondrial membrane, where it is thought to facilitate Drp1 recruitment. Liposome-based assays have shown that CL enhances Drp1’s activity. Although Drp1’s general role in mitochondrial fission is well-established, the molecular mechanism underlying its interaction with CL to promote membrane association and activity remains poorly understood, primarily due to the presence of a disordered region known as the variable domain (VD). This domain has been proposed to interact directly with the membrane, undergoing conformational changes that support Drp1 self-assembly and allosteric activation of GTP hydrolysis. Structural studies to date have either excluded the VD or failed to resolve it. Using coarse-grained molecular dynamics simulations, we are investigating how the VD interacts with membranes of varying lipid composition. This approach will help us explore how lipid environments modulate Drp1 activity in model membranes and ultimately contribute to a deeper understanding of mitochondrial fission regulation.