Some Thoughts on a Mechanism for Cell Suicide

You might not think of cell suicide as a sexy subject - but it is actually quite hot. Cells off themselves for any number of reasons: In embryonic development, cell suicide helps shape the growing organism. In adults, suicide is the last resort of a cell whose DNA is too damaged to repair, and its death prevents cancer, among other things. You can think of cell suicide as a prerequisite for the existence of multicellular life.

Prof. Atan Gross has, for the past several years, been focusing on a pair of cell suicide proteins - BID and ATM. The more Gross studies these proteins, the more complex the picture appears. First, he found that the two are involved in both initiating cell suicide and preventing said suicide. His latest research shows that the same two proteins are also active in a completely different part of the cell's life cycle - either preventing blood stem cells from differentiating or prompting them to differentiate. And there are hints that a much more convoluted set of connections may be lurking just outside the scope of his present framework.

Yet at the very heart of the story is a simple switch - an on-off connection between BID and ATM. ATM acts as a physical restraint on BID: When it stays around the cell nucleus, the status quo is maintained. When the two don't connect, the unleashed BID molecule goes off to another organelle - the mitochondrion - where the small, destructive molecules known as reactive oxygen species are produced.  An excess of reactive oxygen species both kills the cell and initiates the differentiation of new replacement cells. To use an engineering concept, Gross describes the BID-ATM mechanism as a rheostat that senses the condition of the cell and regulates reactive oxygen species production accordingly.

That would seem to indicate a neat, elegant suicide mechanism. (Though not terribly simple: The cell nucleus and mitochondria are apparently in cahoots, and two very different activities - suicide and stem cell differentiation - are controlled by the same switch.)

Now for the real complexity: The various proteins in question, including the ones on the mitochondria involved in producing the reactive oxygen species, all have "day jobs," working to maintain such metabolic functions as fat regulation. And here, says Gross, is where the idea of a unique suicide mechanism starts to get fuzzy. Rather than a special "cyanide pill" kept especially for the purpose of self-destruction, the cell does itself in by overdosing on everyday substances. Instead of simple switches, the molecules involved are something like people - they behave differently in different situations and are occasionally driven to desperate acts.

When mild-mannered BID exits the cell nucleus, it initiates cell suicide and saves the organism. But is that the whole story? Illustration: Elite Avni

Does this mean that the elegant model of a rheostat flies out the window? Not exactly. But it might be useful to think of it less as a component - something that can be isolated from a larger piece of machinery - and more as a cycle within a cycle.

Elegant engineering or a small part of a large, highly complex cycle? The question becomes especially relevant once we start to think about fixing or adjusting the mechanism to treat disease. Gross believes that the inherent connection he and his team are uncovering between the suicide switch and cell metabolism may eventually lead to new thinking about treating all sorts of ailments.

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A couple of years back I read Nick Lane's, "Power, Sex, Suicide: Mitochondria and the Meaning of Life." It is good to read the most current thought on the matter. Thank you for posting this.

By Mike Olson (not verified) on 22 May 2012 #permalink