
==== Front
bioRxiv
BIORXIV
bioRxiv
Cold Spring Harbor Laboratory

10.1101/2024.05.21.595226
preprint
1
Article
Cardiolipin clustering promotes mitochondrial membrane dynamics
Zuccaro Kelly E.
Abriata Luciano A.
Meireles Fernando Teixeira Pinto
Moss Frank R.
Frost Adam
Dal Peraro Matteo http://orcid.org/0000-0002-2973-3975

Aydin Halil http://orcid.org/0000-0002-5409-3797

23 5 2024
2024.05.21.595226http://biorxiv.org/lookup/doi/10.1101/2024.05.21.595226
nihpp-2024.05.21.595226.pdf
Abstract

Cardiolipin (CL) is a mitochondria-specific phospholipid that forms heterotypic interactions with membrane-shaping proteins and regulates the dynamic remodeling and function of mitochondria. However, the precise mechanisms through which CL influences mitochondrial morphology are not well understood. In this study, employing molecular dynamics (MD) simulations, we observed CL localize near the membrane-binding sites of the mitochondrial fusion protein Optic Atrophy 1 (OPA1). To validate these findings experimentally, we developed a bromine-labeled CL probe to enhance cryoEM contrast and characterize the structure of OPA1 assemblies bound to the CL-brominated lipid bilayers. Our images provide direct evidence of interactions between CL and two conserved motifs within the paddle domain (PD) of OPA1, which control membrane-shaping mechanisms. We further observed a decrease in membrane remodeling activity for OPA1 in lipid compositions with increasing concentrations of monolyso-cardiolipin (MLCL). Suggesting that the partial replacement of CL by MLCL accumulation, as observed in Barth syndrome-associated mutations of the tafazzin phospholipid transacylase, compromises the stability of protein-membrane interactions. Our analyses provide insights into how biological membranes regulate the mechanisms governing mitochondrial homeostasis.

Teaser

This study reveals how CL modulates the activity of OPA1 and how MLCL impacts its ability to govern mitochondrial function.
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pmc
