(This is a repost of content first appearing on the old Running Primate blog. I dug this up as optional work for my high school biology students so I thought I'd repost here.)
Mitochondria are the tiny bacteria-turned-organelles (no kidding!) that took up residence in complex cells 1.5 billion years ago and have been nearly ubiquitous since. They comprise significant volumes of cell types that require huge energy supplies, such as animal skeletal muscle. The evolution of human endurance, then, owes much to our little friends who your biology teacher correctly but disaffectedly called "the powerhouse of the cell". (Never mind that this parroted aphorism confuses the plural "mitochondria" for the singular "mitochondrion".) Now that we all agree on this important point re: mitochondria being the powerhouse of the cell, it should surprise you to hear that mitochondria are inefficient. Purposefully, adaptively so.
When provided with oxygen (that you breathe) mitochondria are the final and by far the most productive link in the biochemical chain that converts the energy from your food into ATP, which are molecules that transfer energy for muscle contraction and other functions. So, with regard to human endurance capacity, mitochondria's role is to convert food energy into a form (ATP) useful to muscle fibers. Mitochondria have traditionally been depicted as bean-shaped but recent research reveals that they are highly varied in shape and other properties depending on their specific location within the muscle cell (see picture above). Endurance training increases the number and volume of muscle mitochondria, enabling the muscle to better convert carbohydrate and fat substrates into ATP for muscle contraction.
How is the energy from food molecules--namely, carbohydrates and fats-- converted into ATP for muscles to use? The entire process is termed "cellular respiration" and is the subject of a week in my biology class but needn't be reviewed here. Let's jump to the mitochondria part. Essentially, the energy in the food you eat reaches mitochondria in the form of electrons attached to molecules called NADH and FADH2. At the mitochondria's inner membrane, these 2 molecules give up these electrons, releasing energy that is used to pump hydrogen ions (H+) across said membrane. As H+ ions build up on the outside of this membrane, most return back through via a membrane protein called ATP synthase. As they flow through this protein, they drive the production of ATP molecules, which can then be used by the cell for numerous energy-consuming activities, including muscle contraction. All of this is depicted below.
Clearly, it would be fantastic for muscle contraction efficiency if all of the energy in carbohydrates and fats was converted to ATP production. But it's not. Note the red protein on the far right, labelled "leak". This represents several different proteins that are known to permit (even encourage) some H+ ions to flow back into the mitochondrial matrix without contributing to ATP production. These proteins have been identified in certain cell types, such as brown fat tissue, which contains lots of uncoupling protein 1 (UCP1), a protein that actively encourages H+ leak. This leak is also called uncoupled respiration (UCR). Why do mitochondria in fat cells permit this uncoupled respiration? Because when H+ ions leak back into the mitochondrial matrix, bypassing ATP synthase, they generate heat. Mammals have this process to thank for our endothermy, for our ability to generate our own body heat. In fact, rats spend up to 25% of their calories on this process, instead of producing ATP for cell processes. And it's important for human mammals too: studies of human mitochondrial DNA variation show that mitochondria of arctic peoples have been shaped to increase UCR and generate more body heat.
But it would be stupid if this process occurred in skeletal muscle, right? It's great to stay warm and maintain homeostasis, but surely skeletal muscle should direct all available energy to ATP production, thus powering muscle contraction. Nay. There's good evidence that mitochondria in human skeletal muscle cells also permit UCR. When exercising at a constant power output and constant blood lactate concentration (a marker of the relative contribution of aerobic/anaerobic energy production), oxygen consumption continues to rise, suggesting partial uncoupling in mitochondria (this is termed "VO2 drift"). Proteins analogous to brown fat tissue's UCP1 have been found muscle, including UCP3, but studies have not demonstrated conclusively that it permits H+ leak. Other proteins involved in other processes are also candidates. Research shows that UCR decreases after 6 weeks of endurance training, perhaps due to decreases in UCP3 expression. This can be interpreted as an adaptive response to avoid generating excess body heat (more mitochondria thanks to training = higher potential for heat generation from UCR), or perhaps (I'd suggest) a response intended to minimize wasted energy. After all, a muscle subjected to repeated workloads should respond by increasing its efficiency, and decreasing UCR makes sense.
Uncoupled respiration in skeletal muscle remains poorly understood. It probably serves other purposes, especially the reduction of reactive oxygen species (ROS, or "free radicals"), which accumulate from normal, ATP-generating H+ flow. Why skeletal muscle permits uncoupled respiration and how endurance training mediates this activity can inform the study of how human endurance evolved. It's also important to tease out differences between cell types. Studies examining differences in human mitochondrial DNA between populations, like the one linked in the 4th paragraph, cannot account for gene expression. That is: most of your cells have mitochondria, and they all have the same mitochondrial DNA. But skeletal muscle cells are likely expressing these genes differently than, say, brown fat cells. Understanding differences in UCR between cell types--especially in skeletal muscle-- will inform the evolution of endurance.
Rock on, powerhouses of the cell. Even if you are purposefully inefficient.
4/10/16 update Ah, the power of simply doing a bit more Google Scholar searching. The question I posed above-- whether the uncoupling genes that differ between populations are expressed in muscle tissue or just fat tissue-- has been investigated a bit. Just last November 2015 there was a Scandinavian study (here--sorry, full text is behind a paywall) looking at differences in uncoupled oxphos in the muscles of Inuit and Danish folk. The Danish subjects completed a 42-day skiing trek and data was taken afterwards to measure the effects of physiological (vs. evolutionary) adaptation to the cold. Uncoupled respiration was no different in the skeletal muscle tissue between Inuit and Danes (pre and post trek). Lots of interesting (though mostly expected) changes occurred in the muscle tissue, and the discussion section is worth a read as the authors make interesting comparisons to the physiological adaptations that occur due to altitude. So this is preliminary though compelling evidence that the uncoupling genes found to differ between arctic and non-arctic populations (see the papers linked earlier in my blog post) aren't expressed in all cell types. I'd say it's likely that these genes are expressed only in adipose (brown and maybe white, or "beige") tissue; skeletal muscle doesn't uncouple in response to cold, because efficient ATP production in the face of repeated exercise is too important to compromise. As the authors conclude: "...the preserved coupling in muscle tissue suggests evolutionary selection for conservation of energy over heat production at the level of muscle mitochondria despite the extreme cold of the arctic winter. The results on skeletal muscle do not exclude the possibility that evolutionary cold adaptation may alter coupling and thus thermoregulatory mechanisms in other tissues....Accordingly, it would be of great interest to investigate whether climatic selection for haplogroup manifests functionally in other tissues such as adipocytes..."
References Divakaruni, A. S., & Brand, M. D. (2011). The regulation and physiology of mitochondrial proton leak. Physiology, 26(3), 192-205.Fernström, M., Tonkonogi, M., & Sahlin, K. (2004). Effects of acute and chronic endurance exercise on mitochondrial uncoupling in human skeletal muscle. The Journal of physiology, 554(3), 755-763Mishmar, D., Ruiz-Pesini, E., Golik, P., Macaulay, V., Clark, A. G., Hosseini, S., ... & Sukernik, R. I. (2003). Natural selection shaped regional mtDNA variation in humans. Proceedings of the National Academy of Sciences,100(1), 171-176.Rolfe, D. F., Newman, J. M., Buckingham, J. A., Clark, M. G., & Brand, M. D. (1999). Contribution of mitochondrial proton leak to respiration rate in working skeletal muscle and liver and to SMR. American Journal of Physiology-Cell Physiology, 276(3), C692-C699Ruiz-Pesini, E., Mishmar, D., Brandon, M., Procaccio, V., & Wallace, D. C. (2004). Effects of purifying and adaptive selection on regional variation in human mtDNA. Science, 303(5655), 223-226.