Programmed cell death: Solid-state NMR insights

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  • Published: Apr 1, 2019
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Programmed cell death: Solid-state NMR insights

Apoptosis insights

When mitochondria are damaged, cytochrome c can induce a signal that leads to apoptosis. | Illustration Patrick van der Wel and Mingyue Li

Researchers from The Netherlands and the USA have used solid-state nuclear magnetic resonance (NMR) spectroscopy to show how the signal induced by the enzyme cytochrome C is more controlled than was originally anticipated. The discovery could have implications for understanding how mitochondria work and how they go awry in certain diseases, as well as leading to new insights in apoptosis, programmed cell death, which is also involved in diseases such as cancer.

When cells go wrong, the body needs to dispose of them before they cause harm. However, when the disposal system itself goes wrong, disease can arise. There are various biochemical signals that can drive the self-destruct process through apoptosis. However, if apoptosis runs amuck, then progressive neurodegenerative disease, such as Huntington’s disease, can arise. If apoptosis fails we often see cancer develop.

Strong signals

One of the strong signals for apoptosis is the oxidation of cardiolipin, a phospholipid that is only present in the membrane of mitochondria, often known colloquially as the cell’s energy factories. "Mitochondria have two membranes and this cardiolipin is primarily present in the inner membrane," explains Patrick van der Wel of the University of Groningen. "When it is oxidized and moves to the outer membrane, it will trigger apoptosis."

There are experimental drugs that inhibit this oxidization process and have been shown to slow the progression of Huntington’s disease in animal models. However, cytochrome C accelerates the oxidation process. "This suggests that the oxidation event is not accidental but may also act as a useful and desirable signal for the cell," explains Van der Wel. He and his team hoped to understand how this enzymatic oxidization occurs and used solid-state NMR spectroscopy, which allows them to study membrane-bound proteins in a way that is usually off-limits to crystallographic methods. The team thus compared cytochrome C in solution with membrane-bound cytochrome C to see how interaction with the membrane altered its structure.

Expectations

"We expected that the protein would be inside the membrane, in an unfolded state that exposes the reactive haem group," Van der Wel explains. The haem would then be ready to oxidize the cardiolipin. However, their data showed something very different. "The enzyme doesn’t enter the membrane but is bound to membrane domains containing cardiolipin, and it remains folded. However, a protein loop covering the haem group will sometimes move aside, exposing the phospholipids to the haem group," he adds.

This finding hints that cardiolipin activity in apoptosis is regulated in some way and is not simply a passive response to oxidative conditions. This opens up a new target for drug discovery.

Related Links

Struct 2019, online: "Surface-Binding to Cardiolipin Nanodomains Triggers Cytochrome c Pro-apoptotic Peroxidase Activity via Localized Dynamics"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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