Cardiolipin, and not monolysocardiolipin, preferentially binds to the interface of complexes III and IV

Area of Science:

• Mitochondrial biology
• Lipid biochemistry
• Molecular biophysics

Background:

• Mitochondrial supercomplexes, formed by protein complexes in the inner mitochondrial membrane, are crucial for ATP production via oxidative phosphorylation.
• Cardiolipin (CL) stabilizes these supercomplexes, while its variant, monolysocardiolipin (MLCL), accumulates in Barth syndrome (BTHS), leading to impaired mitochondrial function.
• The precise mechanisms by which MLCL causes BTHS pathogenesis remain elusive.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying MLCL-induced mitochondrial dysfunction in Barth syndrome.
• To characterize the differential interactions of CL and MLCL with mitochondrial supercomplexes.

Main Methods:

• Multiscale molecular dynamics simulations were employed to investigate CL and MLCL interactions with yeast and mammalian mitochondrial supercomplexes (Complex III-Complex IV).
• Coarse-grained simulations identified binding sites, while free energy perturbation calculations quantified interaction strengths.
• Atomistic contact analyses detailed specific molecular interactions at the complex interface.

Main Results:

• Both CL and MLCL bind to the interface between Complex III (CIII) and Complex IV (CIV) within supercomplexes.
• MLCL exhibits weaker interactions compared to CL, primarily due to reduced contacts with CIV.
• CL acts as a more effective 'glue' stabilizing the CIII-CIV interface than MLCL.
• This interaction interface is conserved across yeast and human supercomplexes.

Conclusions:

• MLCL accumulation in Barth syndrome disrupts mitochondrial supercomplex stability by forming weaker interactions at the lipid binding site between CIII and CIV.
• This destabilization contributes to the abnormal mitochondrial bioenergetics observed in BTHS patients.