Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1

Area of Science:

• Mitochondrial biology
• Membrane biophysics
• Structural biology

Background:

• Cardiolipin (CL) is crucial for mitochondrial function and morphology.
• Its precise role in regulating mitochondrial shape via protein interactions remains unclear.
• Mitochondrial dynamics involve complex protein-lipid interactions.

Purpose of the Study:

• To elucidate the mechanism by which cardiolipin (CL) influences mitochondrial morphology.
• To investigate the interaction between CL and the mitochondrial fusion protein Optic Atrophy 1 (OPA1).
• To understand the impact of CL lipid composition changes on OPA1 function.

Main Methods:

• Molecular dynamics (MD) simulations to observe CL localization near OPA1.
• Development of a bromine-labeled CL probe for enhanced cryo-electron microscopy (cryoEM) contrast.
• CryoEM structural analysis of OPA1 assemblies bound to CL-containing lipid bilayers.

Main Results:

• CL was observed to localize near the membrane-binding sites of OPA1.
• Direct evidence of CL interaction with conserved motifs in OPA1's paddle domain was obtained.
• Reduced OPA1 membrane remodeling activity was observed with increasing monolyso-cardiolipin (MLCL) concentrations.
• Compromised protein-membrane interaction stability was suggested with CL to MLCL conversion.

Conclusions:

• CL directly interacts with OPA1, regulating its membrane-shaping capabilities.
• Changes in CL lipid composition, such as MLCL accumulation, can impair OPA1 function.
• These findings offer insights into mitochondrial homeostasis regulation by biological membranes.