Surface-Binding to Cardiolipin Nanodomains Triggers Cytochrome c Pro-apoptotic Peroxidase Activity via Localized Dynamics
Open accessAbstract
The peroxidation of cardiolipins by reactive oxygen species, which is regulated and enhanced by cytochrome c (cyt c), is a critical signaling event in mitochondrial apoptosis. We probe the molecular underpinnings of this mitochondrial death signal through structural and functional studies of horse heart cyt c binding to mixed-lipid membranes containing cardiolipin with mono- and polyunsaturated acyl chains. Lipidomics reveal the selective oxidation of polyunsaturated fatty acid (PUFA) cardiolipin (CL), while multidimensional solid-state NMR probes the structure and dynamics of the membrane and the peripherally bound protein. The hydrophilic milieu at the membrane interface stabilizes a native-like fold, but also leads to localized flexibility at the membrane-interacting protein face. PUFA CL acts as both a preferred substrate and a dynamic regulator by affecting the dynamics of the cyt c N70-I85 Ω loop, which covers the heme cavity.
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In most severe cases, cardiolipin stimulates the release of cytochrome c and precipitates apoptosis.
“In most severe cases, cardiolipin stimulates the release of cytochrome c and precipitates apoptosis (80).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [80]
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References 68 · Cited by 41
- Authors
- Li, M., Mandal, A., Tyurin, V. A., DeLucia, M., Ahn, J., Kagan, V. E., & van der Wel, P. C. A.
- Affiliations
- University of Pittsburgh (US)
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 27
- Issue
- 5
- Pages
- 806-815.e4
- ISSN
- 0969-2126 (ISSN-L)
- PMC
- PMC6615723
- OpenAlex
- W2920927378
- Cited by
- 41
- References
- 68
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 2 · 2023: 6 · 2022: 7 · 2021: 7 · 2020: 5 · 2019: 4
- FWCI
- 1.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Structure (publishedVersion, other-oa)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- NIH (R01 GM113908, P01 HL114453, U19AI068021, S10 OD012213-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- cytochrome c, cardiolipin, mitochondrial apoptosis, peroxidase activity, polyunsaturated fatty acids, lipid oxidation, reactive oxygen species, membrane nanodomains, protein-lipid interactions, heme cavity, membrane interface, lipidomics, solid-state NMR
- MeSH terms
- Protein Domains, Lipidomics, Animals, Cardiolipins, Cell Membrane, Fatty Acids, Unsaturated, Heme, Horses, Myocardium, Magnetic Resonance Spectroscopy, Oxygen, Peroxidases, Protein Conformation, Apoptosis, Protein Folding, Nanotechnology, Cytochromes c
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