by Kirk Beebe

As research showing the intimate connection between metabolism (aka biochemistry) and higher-order cellular function mounts, I am simultaneously excited and puzzled. I get excited by new metabolism research and enthusiastically embrace the importance of it. But, I am often bewildered that, in this gene-centric world, not everyone gets as charged as I do.

While many of you reading this post may share my enthusiasm, some of you may regard metabolism as an “old dog” with an established set of tricks. I am convinced that if you were presented with the information I have seen, you would be comparably enthusiastic and agree that metabolomics and metabolism research are an important avenue for addressing many important life science questions. (McKnight, 2010)

dog.pngFor a cell to move, change shape, repair, signal, grow, divide and make things like DNA, metabolism and its central metabolic organelle - the mitochondria - must be coordinately engaged. In other words, for the cell to do almost anything, it requires a “hall pass” from metabolism. And, the idea that something like a mitochondria would be this automaton for blindly making energy without regard to the function of the rest of the cell (particularly when the rest of the cell encodes the majority of mitochondrial proteins) seems at a minimum, counter intuitive. 

Changing views
Because the last 30 years of training have been focused on molecular biology, many scientists today view metabolism as a drone for making the cell’s energy. In fact, I have to confess that I once had the same view. I was happily pursuing some fundamental molecular biology questions, and when metabolism entered the picture, I took very little notice of how it might be connected to a wider biological picture. 

Today, I realize how naively disconnected my views were. Examples of a more sophisticated role for metabolism in driving or coordinating higher-order cellular or nuclear functions have come to light these last few years. A couple of very recent publications provide particularly vivid illustrations. 

The old dog and new tricks
Regulation of gene expression is essential for all cellular functions, and nearly every action a cell takes requires coordination with metabolism. Taking cues from the environment, the cells respond accordingly – all of these responses require changes in metabolism and coordination with gene expression. It’s a no-brainer, right? Therefore, there must be redundant and very precise routes for coordination. In addition to what has already been uncovered about gene regulation and intermediary metabolism (beautifully reviewed by Gut & Verdin, 2013), there surely are additional very precise pathways that add to this coordinated regulation.

Published in 2014 in Cell, Sutendra, et al. showed how nuclear and mitochondrial functions are coordinated. They demonstrated an elegant connection between the mitochondrial pyruvate dehydrogenase complex (PDC) and regulation of nuclear gene expression. This complex makes the universal acetyl donor, acetyl-CoA. Results show that the entire complex moves from the mitochondria to the nucleus under a specified set of cellular states. 

Why does it do this? It does so to directly provide acetyl-CoA for histone acetylation and epigenetic regulation. Essentially, these researchers uncovered another example of complex mitochondrial-nuclear communication and offered an additional data point or reminder that metabolism is not simply a mindless furnace that supplies energy (ATP).

This last point that metabolism (or in this particular case, the mitochondria) is not just a mindless drone making energy was thunderously echoed in a “blow your hair back” example of how much we have yet to learn about metabolism. 

Two articles in the July 30th issue of Cell by Birsoy et al. and Sullivan et al. provided an astonishing surprise about the fundamental role of the mitochondria in proliferating cells such as immune cancer cells. While it has been accepted for decades that the crucial function of the mitochondria (the electron transport chain, specifically) in proliferating cells is to produce ATP, these papers showed that this is not the case. 

The role instead is to produce a single amino acid, aspartate. The papers elaborate elegantly on the precise mechanistic rationale, but the straight-forward functional rationale is to support the biosynthetic demands of making more cells. Although energy is important, the canary in the coal mine for proliferating cells is this single amino acid.

These findings exemplify that the “old dog” called metabolism has many new tricks to show us. In an era where systems biology is embraced, these examples remind us how integrated a system a single cell is and that there are no operational silos.