Studies of the cardiolipin interactome

Fox, Colin A.; Ryan, Robert O.

doi:10.1016/j.plipres.2022.101195

Cited by 11 publications

(6 citation statements)

References 84 publications

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“…Association of CL with the inner mitochondrial membrane has been implicated in its prominent role sustaining mitochondrial bioenergetics through affecting membrane-binding of cytochrome c , enzyme complexes of the TCA cycle, and those catalyzing oxidative phosphorylation. 31 , 32 Previous studies have emphasized that the acyl-chain composition of negatively charged CL is correlated with the stability and coordinated functions of ETC complexes and mitochondrial GTPases. 20 , 21 , 22 , 33 , 34 Accumulating evidence has suggested that CL molecular species are critical in the interaction and assembly of respiratory supercomplex subunits present in the mitochondrial inner membrane and in the matrix.…”

Section: Discussionmentioning

confidence: 99%

Genetic deletion of skeletal muscle iPLA2γ results in mitochondrial dysfunction, muscle atrophy and alterations in whole-body energy metabolism

et al. 2023

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Section: Discussionmentioning

confidence: 99%

Genetic deletion of skeletal muscle iPLA2γ results in mitochondrial dysfunction, muscle atrophy and alterations in whole-body energy metabolism

et al. 2023

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“…However, the fact that SPN10 showed the highest in vitro efficacy while also having the weakest preference for CL suggests that CL protection may not be the primary mechanistic benefit of MTPs. It may even be possible that reduced interaction with CL (after the initial electrostatic attraction to the bilayer) is a benefit, potentially freeing up CL lipids to interact with the many IMM-associated proteins that require CL for optimal functioning and/or assembly. − …”

Section: Resultsmentioning

confidence: 99%

Peptide Power: Mechanistic Insights into the Effect of Mitochondria-Targeted Tetrapeptides on Membrane Electrostatics from Molecular Simulations

Tamucci,

Alder,

May

2023

Mol. Pharmaceutics

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Mitochondrial dysfunction is implicated in nine of the ten leading causes of death in the US, yet there are no FDAapproved therapeutics to treat it. Synthetic mitochondria-targeted peptides (MTPs), including the lead compound SS-31, offer promise, as they have been shown to restore healthy mitochondrial function and treat a variety of common diseases. At the cellular level, research has shown that MTPs accumulate strongly at the inner mitochondrial membrane (IMM), slow energy sinks (e.g., proton leaks), and improve ATP production. Modulation of electrostatic fields around the IMM has been implicated as a key aspect in the mechanism of action (MoA) of these peptides; however, molecular and mechanistic details have remained elusive. In this study, we employed all-atom molecular dynamics simulations (MD) to investigate the interactions of four MTPs with lipid bilayers and calculate their effect on structural and electrostatic properties. In agreement with previous experimental findings, we observed the modulation of the membrane surface and dipole potentials by MTPs. The simulations reveal that the MTPs achieve a reduction in the dipole potential by acting to disorder both lipid head groups and water layers proximal to the bilayer surface. We also find that MTPs decrease the bilayer thickness and increase the membrane's capacitance. These changes suggest that MTPs may enhance how much potential energy can be stored across the IMM at a given transmembrane potential difference. The MTPs also displace cations away from the bilayer surface, modulating the surface potential and offering an alternative mechanism for how these MTPs reduce mitochondrial energy sinks like proton leaks and mitigate Ca 2+ accumulation stress. In conclusion, this study highlights the therapeutic potential of MTPs and underlines how interactions of MTPs with lipid bilayers serve as a fundamental component of their MoA.

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“…Altered cristae formation has previously been linked to cytochrome c release, where mutations in a protein that forms part of the mitochondrial contact site and cristae organizing system (MICOS) caused a more open cristae conformation that facilitated cytochrome c release 89 , however, we did not observe changes to cytochrome c abundance in the mitochondria. Cristae structures in the mitochondrial inner membrane are critical for ATP production via the ETC 86 , and CLs are required for efficient cristae packing and stabilisation of ETC complexes 58 . Furthermore, changes in CL content and cristae morphology within the IMM have previously been shown to influence mitochondrial ATP production 83,90,91 .…”

Section: Discussionmentioning

confidence: 99%

“…CLs are associated with many aspects of mitochondrial biology, including ROS regulation, cytochrome c-related cell death signalling and energy production [85][86][87] . Accordingly, we assessed mitochondrial ROS production and found that it was increased under ELOVL5 knockdown, and that exogenous cVA supplementation partially rescued this effect.…”

Section: Discussionmentioning

confidence: 99%

Cis-vaccenic acid is a key product of stearoyl-CoA desaturase 1 and a critical oncogenic factor in prostate cancer

Scott,

Young,

Quek

et al. 2024

Preprint

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Altered monounsaturated fatty acid (MUFA) metabolism is a hallmark of oncogenic transformation. Recently, the MUFA cis-vaccenic acid (cVA) was identified as a putative regulator of prostate cancer cell viability. cVA production requires the activity of stearoyl CoA desaturase 1 (SCD1), an enzyme frequently dysregulated in cancer, but the role of cVA in regulating cancer cell phenotypes has not been extensively explored, compared with the more commonly studied product and structural isomer of cVA, oleic acid. Here, we utilised SCD1 inhibition to study the effects of cVA in prostate cancer cells. We found that cVA consistently rescues reductions in cell viability due to SCD1 inhibition and promotes cell growth under normal conditions, thereby identifying cVA as an important and previously unrecognised product of SCD1 in prostate cancer. More broadly, we demonstrate that individual MUFA species exert a diverse range of influence on oncogenic phenotypes, highlighting a need to more precisely characterise the lipidome of cancer cells to understand the molecular pathology of the disease.

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Studies of the cardiolipin interactome

Cited by 11 publications

References 84 publications

Genetic deletion of skeletal muscle iPLA2γ results in mitochondrial dysfunction, muscle atrophy and alterations in whole-body energy metabolism

Genetic deletion of skeletal muscle iPLA2γ results in mitochondrial dysfunction, muscle atrophy and alterations in whole-body energy metabolism

Peptide Power: Mechanistic Insights into the Effect of Mitochondria-Targeted Tetrapeptides on Membrane Electrostatics from Molecular Simulations

Cis-vaccenic acid is a key product of stearoyl-CoA desaturase 1 and a critical oncogenic factor in prostate cancer

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