Metabolism: the Matryoshka dolls of life

Definition:

The Cambridge Dictionary defines metabolism as “all the chemical and physical processes by which a living thing uses food for energy and growth” (Cambridge Dictionary, 2025). Albeit correct, I´ve always found this definition alienating. To those that tremble at the thought of amino-acid sequences, differential equations and physical laws. Such as yours truly. Perhaps even more importantly, this definition underscores metabolism´s role as the backbone of life itself. These reactions occur, and they have to occur, to sustain every single event that takes place inside our bodies. Every muscle twitch, every sense we feel, every thought that comes through our heads, can only take place because of the metabolic machinery that is working, underneath it all, to support it. And, when those events no longer occur, life as we know it ceases to exist. And there is no subject more invested in the study of the way in which living things exist than biology itself.

Metaphor:

Besides underscoring its biological implications, this definition can easily evoke a sense of linearity. It almost suggests that, so long as the system receives the necessary inputs (nutrients), a series of sequentially connected reactions will occur to reach the desired outcome (the production of molecules). So far, so good. But if metabolic processes were so linear, then one could assume that to crack one means to crack them all. So long as scientists identify which input is lacking, the introduction of that molecule should allow for the processes that power the system to go ahead. Since physical laws aim to describe fundamental processes, this should apply in every conceivable biological context too – and it’s hard to think of a more fundamental process than life itself. Yet, metabolism may be better understood as an ensemble of Matryoshka dolls.

If you´ve never come across a Matryoshka doll, you are first faced with an intricate pattern of shapes and colors, all making up a woman dressed in her traditional attire. Depending on your preferences, you might pay more attention to the hair, the floral composition that makes up her dress, the mantle embracing her shoulders. The feature in question does not matter, so long as you pay enough attention to it to think you´ve understood it. Some might even dare to predict how the rest of the set will look based on this initial understanding. Such as yours truly.

But then, you open the second doll and, although recognizable, this woman looks quite different from the first representation you encountered. She’s a blonde, the flowers in her dress are now smaller, her mantle is of a completely different color. If the betting woman in you is still there, you will reframe your prediction for the next doll based on this new information. The flowers and the mantle have changed, but they are still there, so you assume they are intrinsic features of the dolls, likely to persist within the next layer.

So, you open the doll once again. But the sense of uncertainty creeps on just as swiftly. Not only were your predictions wrong, but new features are now important to this representation of the doll. The mantle is gone, the multitude of flowers have morphed into a single rose across the woman´s dress, her cheeks are blatantly covered in blush.

Now, if asked to choose a feature most intrinsic to this Matryoshka doll, what would you choose? And, regardless of your choice, would you agree with someone describing the dolls as serial representations of the same woman? I don´t think so.

Indeed, the characteristics of metabolic pathways across the distinct levels of biological function eerily resemble those of the Matryoshka dolls. At the most superficial level, our body is dependent on the activation of the metabolic machinery responsible for the consumption of glucose. These pathways are engaged to generate molecules that store energy (catabolism) and molecules that are needed to build other molecules (anabolism). Besides vitamins and fiber, our body also requires lower levels of fats and proteins, mostly for the purposes of obtaining their essential units (fatty acids and amino acids), which are awfully inefficient to produce from glucose. From this first metabolic representation, you would astutely assume that targeting the metabolic machinery powering glucose metabolism should restore most metabolic conditions.  However, as you move to the second level of biological function (individual organs), the metabolic landscape changes.  You find organs that are disproportionally dependent on glucose, such as the brain: just 2% of your body weight accounts for almost 60% of your glucose catabolism, or 20% of your whole-body baseline metabolism (Nutrient Metabolism, Human | Learn Science at Scitable, n.d.). The remaining organs have no other choice but to adapt to this new feature: the liver and skeletal muscle, arguably two of the most metabolically active organs, highly rely on fatty and amino acid catabolism to sustain their functions. So, what was not so important from the first representation of our body now becomes vital for the correct functioning of this layer. Sound familiar? Just as with the Matryoshkas, prepare to be surprised.

Once you dive into the cell types that make up the brain, the next biological layer of that glucose-reliant organ, a new feature emerges (Ioannou et al., 2019).  Despite being mostly dependent on it, neurons are particularly vulnerable to a by-product of glucose catabolism, reactive oxygen species (ROS for Friends).  A new important feature you may ask? Yes indeed. At first, neurons are capable of producing anti-oxidant molecules to neutralize ROS, and balance to the force has been restored. However, once neurons become stressed, they simply can´t keep up with ROS, which is now free to corrupt (oxidize) fatty acids. To adapt to this self-inflicted challenge, neurons release fatty acids, which are readily taken up and catabolized by astrocytes, a supportive cell type of the brain.  So, in this glucose-reliant organ, not only do we have a cell type that mainly relies on fatty acid catabolism (astrocytes), but the reason it does so is to protect neurons from the consequences of a new feature (ROS) that arises due to excessive glucose consumption!

Who could have foreseen that from whole-body metabolic measurements? Not yours truly, that’s for sure. But then again, that’s (metabolic) life.

References:

Cambridge Dictionary. (2025, March 26). Metabolism. https://dictionary.cambridge.org/dictionary/english/metabolism

Ioannou, M. S., Jackson, J., Sheu, S.-H., Chang, C.-L., Weigel, A. V., Liu, H., Pasolli, H. A., Xu, C. S., Pang, S., Matthies, D., Hess, H. F., Lippincott-Schwartz, J., & Liu, Z. (2019). Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity. Cell, 177(6), 1522-1535.e14. https://doi.org/10.1016/j.cell.2019.04.001

Nutrient Metabolism, Human | Learn Science at Scitable. (n.d.). Retrieved 28 March 2025, from https://www.nature.com/scitable/topicpage/dynamic-adaptation-of-nutrient-utilization-in-humans-14232807/