So many ways to die

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(Dev Cell, Jan 2014) Scientists discover how cells coordinate their nuclear response to stress with early steps in the execution of programmed cell death.

Many of the decisions that a cell has to make revolve around the following question: “How do I survive the various attacks and stresses from the outside so that I can carry on with my job?”. To accomplish this, multiple defense mechanisms combat bacteria, virus, radiation or carcinogens to help protect the precious DNA inside the cell. At the same time, several control systems ensure that damaged or defective cells that are detrimental to neighbors and the organism are removed. Thus, some cells carry out a program for cell death.

To accomplish programmed cell death, several things can happen. Some cells ask for help by the surroundings, and are absorbed by nearby tissue. Other cells are shed from the surface and disappear, while some coordinate an inner destruction process. A recent article in Developmental Cell provides a new understanding to how this last example may be coordinated between various compartments in the cell [1]. In response to stress, yeast cells initiate a set of changes both on their DNA and outside the nucleus, and researchers have now described a novel role for in this coordination.

Katrina Cooper, the lead author on the study, explains how cyclin C can accomplish this. “Before this nuclear protein is destroyed, it is exported to the cytoplasm where it associates with the outer membrane of the and promotes stress induced as a prelude to programmed cell death.”

Importantly, fission of mitochondria is a key mediator of programmed cell death, as this releases messenger molecules such as cytochrome c to initiate cellular destruction. What the efforts of Dr. Cooper’s team could show is that when cyclin C is exported out of the nucleus to be destroyed, it briefly associates with the outer mitochondrial membrane just prior to its destruction. Here, it acts to recruit and assemble the protein complex required for efficient fragmentation of the mitochondria. The precise details of how this activation occurs is currently unknown, but is actively pursued by Dr. Cooper and her colleagues.

“As most findings in biology, it is probably more complicated than we first imagine,“ she comments, and further explains how there are several open questions regarding the role of cyclin C in programmed cell death. For instance, in addition to coordination between the nucleus and the mitochondria, there may also be other parallel mechanisms that contribute to the precise and tight regulation of programmed cell death. Dr. Cooper states that “cross-talk between cellular organelles appears to be the rule rather than the exception”, and she and her team are actively pursuing lines of investigation to identify and characterize novel contact-points between various cellular compartments.

One central aspect of basic biology is to investigate whether regulatory mechanisms are conserved between model organisms and humans. This allows findings from basic research to be translated into concepts that might be of interest or importance to human health and disease. Importantly, cyclin C functions to protect cell populations from allowing a damaged cell to proliferate and, in this way, it may function as a potential . Perhaps cyclin C may play an important role in preventing damaged cells from accumulating and get out of control in some cancer types, and thus provide insight to novel diagnostic or therapeutic options?

Together, the findings reported in by Dr. Cooper and her colleagues uncovers an unexpected role for coordination of defense mechanisms by cyclin C that is of importance to understand how a cell protects itself and others from stress and damage.

Åsmund Husabø Eikenes

[1] Cooper KF, Khakhina S, Kim SK, Strich R. Stress-Induced Nuclear-to-Cytoplasmic Translocation of Cyclin C Promotes Mitochondrial Fission in Yeast. Dev Cell. 2014 Jan 27;28(2):161-73. doi: 10.1016/j.devcel.2013.12.009.

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Cyclins are proteins that undergo rapid degradation and re-synthesis in response to various cellular events, such as stress or cell division. They bind to specific partners inside the cell, to switch their function on or off, and are involved in activation and regulation of diverse cellular processes.
Mitochondria are one of the most important organelles within cells. Organelles (meaning “little organs”) are specialized compartments within cells that carry out a specific function. Thus, mitochondria are commonly referred to as a cell’s powerhouse, because their most famous function is to produce much of the molecular energy used by the cell. Many years ago, however, scientists have also established that mitochondria store signaling molecules that can be released on cue to induce cell death.
Fission, or fragmentation, of mitochondria is accomplished by recruitment of multiple proteins that together tighten and cut the mitochondria into multiple smaller pieces. Although mitochondria are normally drawn as bean-shaped, they are in fact highly elongated, interconnected and dynamic structures. The balance of fusion and fission of this organelle is tightly regulated and maintained to keep a healthy cell.
A tumor suppressor is a protein that normally protects cells from uncontrolled or excessive growth. In the context of cancer, we think of mutations in tumor suppressors as negative for the organism. Cells mutant for tumor suppressor genes lose their ability to withstand damage or stress, and often keep on dividing regardless of damage, leading to the formation of a tumor.

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