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Developmental Biology - Cell Death

How Cytochrome C Triggers Cell Death

Cytochrome C signals when dangerous problems arise in the inner cell membrane...

Cytochrome C is a small enzyme that plays an important role in the production of energy by mitochondria. It is also involved in signaling dangerous problems that warrant apoptosis or programmed cell death. Using solid-state NMR (Nuclear Magnetic Resonance), University of Groningen Associate Professor of Solid-State NMR Spectroscopy, Patrick van der Wel and colleagues from the University of Pittsburgh, have discovered that the signal induced by Cytochrome C is more controlled than expected. Their results are published in the journal Structure.

If cells malfunction, the body wants to get rid of these cells before they do more damage. So, different signals can drive a cell to self-destruct through apoptosis. However, widespread programmed cell death contributes to the onset of neurodegenerative diseases such as Huntington's. And a strong signal that triggers apoptosis is the oxidation of cardiolipin, a phospholipid only present in the membrane of mitochondria, the cell's power stations.
"Mitochondria have two membranes and the cardiolipin is primarily present in the inner membrane. When cardiolipin is oxidized and moves to the outer membrane, it will trigger apoptosis."

Patrick C. A. van der Wel PhD, Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA, USA; Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands.


Cells accelerate the oxidation process through the catalytic activity of Cytochrome C, an enzyme that contains a reactive haem group. "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.
Drugs that prevent oxidization of cardiolipin also reduce cell death and slow progression of Huntington's disease in animal models.

Van der Wel wanted to find out how oxidization of cardiolipin by Cytochrome C takes place by studying the behavior of the enzyme when it interacts with the mitochondrial membrane. To do this, he used solid-state NMR, a technique that allows scientists to study atoms in molecules such as proteins or lipids. Van der Wel compared Cytochrome C in solution with membrane-bound Cytochrome C to see how interaction with the membrane altered its structure.
"The signal from atoms that you measure by means of NMR is affected by the atoms' surroundings. Therefore, a change in the shape of the protein would alter the signal."

Patrick C. A. van der Wel PhD

Protein loop

"We expected that the protein would be inside the membrane, in an unfolded state that exposes the reactive haem group," the haem would then easily oxidize the cardiolipin. However, the results showed something 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."

This observation suggests that the action of cardiolipin in apoptosis is to a certain extent regulated, and not just a passive response to oxidative conditions. This could have implications for diseases in which cell death plays an important role.
'If the active form of Cytochrome C is still folded, it might be possible to develop drugs that stop it from oxidizing cardiolipin.'

Patrick C. A. van der Wel PhD

Another possible point of intervention is the binding of the enzyme to specific membrane domains. And finally, problems with the mitochondria can either induce apoptosis or the less invasive removal of just the affected mitochondrion. "If we could understand how this choice is made, we might be able to influence this process."


The experiments described in the paper were performed at the University of Pittsburgh, where Van der Wel worked prior to his transfer to the University of Groningen last year. He is now building a solid-state NMR group at the Zernike Institute for Advanced Materials, part of the Faculty of Science and Engineering.
'This technique will also be used to study alternative ways of protein folding, for example, the formation of amyloids. These protein aggregates play a role in neurodegenerative diseases but they could also be used to design new functional materials."

Patrick Van der Wel PhD.

Most studies of proteolysis by the ubiquitin-proteasome pathway have focused on the regulation by ubiquitination. However, we showed that pharmacological agents that raise cAMP and activate protein kinase A by phosphorylating a proteasome subunit enhance proteasome activity and the cell’s capacity to selectively degrade misfolded and regulatory proteins. We investigated whether similar adaptations occur in physiological conditions where cAMP rises. Proteasome activity increases by this mechanism in human muscles following intense exercise, in mouse muscles and liver after a brief fast, in hepatocytes after epinephrine or glucagon, and renal collecting duct cells within 5 minutes of antidiuretic hormone. Thus, hormones and conditions that raise cAMP rapidly enhance proteasome activity and the cells’ capacity to eliminate damaged and preexistent regulatory proteins.

• Cytochrome c is a cardiolipin-selective lipid peroxidase in intrinsic apoptosis
• Lipidomics probe oxygenation products of cardiolipin peroxidation in vitro
• Solid-state NMR shows folded, but dynamically perturbed, protein on lipid surface
• PUFA lipid-coupled dynamics of 70–85 ? loop regulate access to heme cavity

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 ? loop, which covers the heme cavity.

Mingyue Li, Abhishek Mandal, Vladimir A. Tyurin, Maria DeLucia, Jinwoo Ahn, Valerian E. Kagan and Patrick C.A. van der Wel.

The authors declare no conflict of interest.

The authors thank Mike Delk for advice and support with the NMR measurements. The authors acknowledge funding support from the NIH R01 GM113908 to P.C.A.v.d.W., P01 HL114453 and U19AI068021 to V.E.K., and NIH instrument grant S10 OD012213-01 for the 750 MHz NMR spectrometer.

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Mar 15, 2019   Fetal Timeline   Maternal Timeline   News  

When mitochondria are damaged, Cytochrome C can induce a signal that leads to apoptosis.
Illustration by Patrick van der Wel and Mingyue Li

Phospholid by Wikipedia