On Thu Feb 18th, Patrick was invited to give a talk in the online Emerging Topics in Biomolecular Magnetic Resonance webinar series. This is a global online seminar series featuring the frontier of research using magnetic resonance spectroscopy (mostly NMR) in biological systems. The webinars are also posted (most of them at least) to the dedicated YouTube channel. Lots of great cutting edge research there!
Patrick presented a combination of published an unpublished research that focused on the studies of how lipid (per)oxidation is catalysed in mitochondria, as part of the mitochondrial apoptotic process. Whilst oxidation of biomolecules (lipids, DNA, proteins) is commonly seen as simply an undesirable negative site effect, recent studies show that in apoptotic mitochondria the process of lipid oxidation is actually being catalysed (and directed!) by a protein-driven enzymatic reaction. We have been studying the underlying molecular events for some years now, resulting in a number of related papers [1-4]. In these papers we initially emphasised how the protein involved (cytochrome c) is surprisingly similar in structure to its native state [1]. In more recent work we are figuring out how this native state is variably “mobilised” in its peroxidase active state, and how this is regulated by the substrate of the peroxidation reaction [3]. This latter story is the focus of the online talk.
The idea of the lipids acting as both substrate and dynamic activator, was introduced in our recent paper in Structure [3]. A paper is forthcoming that will look at this in more detail, with some data shown and discussed in the talk. The talk is now also available on the YouTube channel of the webinar series. (If you go there, hang around for many more interesting talks, including the talk by Roland Riek on automating NMR assignments with new computational approaches, in the same video.)
This research has been supported by funds from the NIH to my group and the group of collaborator Valerian Kagan. The papers below should be available (mostly) as open access, but please requests reprints from us if needed.
Some related papers from the lab:
- Mandal, A.; Hoop, C. L.; DeLucia, M.; Kodali, R.; Kagan, V. E.; Ahn, J.; van der Wel, P. C. A. Structural Changes and Proapoptotic Peroxidase Activity of Cardiolipin-Bound Mitochondrial Cytochrome c. Biophys. J.2015, 109(9), 1873–1884. https://doi.org/10.1016/j.bpj.2015.09.016.
- Our first studies of the CytC-CL complex by ssNMR.
- Mandal, A.; Van der Wel, P. C. A. MAS (1)H NMR Probes Freezing Point Depression of Water and Liquid-Gel Phase Transitions in Liposomes. Biophys. J.2016, 111 (9), 1965–1973. https://doi.org/10.1016/j.bpj.2016.09.027.
- A question was asked about phase transitions. We look at this by ssNMR in this paper. Also earlier work on VDAC may be relevant.
- Li, M.; Mandal, A.; Tyurin, V. A.; DeLucia, M.; Ahn, J.; Kagan, V. E.; van der Wel, P. C. A. Surface-Binding to Cardiolipin Nanodomains Triggers Cytochrome c Pro-Apoptotic Peroxidase Activity via Localized Dynamics. Structure2019, 27 (5), 806-815.e4. https://doi.org/10.1016/j.str.2019.02.007.
- Kagan, V. E.; Tyurina, Y. Y.; Sun, W. Y.; Vlasova, L. L.; Dar, H.; Tyurin, V. A.; Amoscato, A. A.; Mallampalli, R.; van der Wel, P. C. A.; He, R. R.; Shvedova, A. A.; Gabrilovich, D.; Bayir, H. Redox Phospholipidomics of Enzymatically Generated Oxygenated Phospholipids as Specific Signals of Programmed Cell Death. Free Radic Biol Med2020, 147, 231–241. https://doi.org/10.1016/j.freeradbiomed.2019.12.028.
- Talks about the role of purposely catalysed enzymatic lipid peroxidation as a signal in biology.