Electron states, light, and mitochondria

In this article I want to delve a bit deeper into a new chemistry concept I've been exploring recently, and how it helps light promote signaling from the mitochondria to the cell nucleus to regulate circadian genetics.

In chemistry molecules can exist in several different electron states. By far the most common of these is the singlet state which does not include any unpaired electrons, then doublet states which include one unpaired electron, and triplet states which include two unpaired electrons.

Molecular oxygen (O2) is an interesting exception in that at room temperature it exists naturally in the triplet state. Oxygen must be lowered to the standard singlet state before reactions with it can occur. In the body hemoglobin is specifically structured to facilitate this state change to allow oxygen to bind to it (more on that here for anyone interested).

Once hemoglobin releases oxygen it is once again converted from the triplet state to singlet state by binding to the heme iron cores in cytochrome C oxidase. The free electrons and protons from the electron transport chain are then fed in to create water. 

Since this conversion of oxygen to the singlet state require a change in its electron structure, it is fairly "rate limited" by its affinity to heme outside of this state. It turns out that light in the infrared spectrum actually enhances the ability of cytochrome C oxidase to convert oxygen into the singlet state, allowing it to bind oxygen more efficiently, and by proxy increasing ATP production.

Since oxygen is the final component in creating the negative charge gradient that keeps electrons flowing in the right direction through the electron transport chain, this stimulation of cytochrome C oxidase ends up "pulling" electrons through the rest of the chain more quickly as well. This paper is a great overview of this process.

While the ability of infrared light to drive the conversion from triplet state oxygen to singlet state at cytochrome C oxidase does not produce any free radicals, there is another way this conversion can occur which does. This involves the use of photosensitizers. 

Photosensitizers work by absorbing light frequencies (think chromophores) and transferring the energy absorbed from that light to other molecules, usually in the form of electron transfer or impacts on hydrogen. These molecules can have interesting effects on the levels of free radicals in mitochondria.

As I've mentioned before, free radicals are not all bad. A free radical is just a molecule with an unpaired electron making it more reactive. These molecules can cause damage to lipid membranes, proteins, etc, in excess, but they are also used by the mitochondria to signal to the nucleus. 

For example, infrared light stimulates the flow of electrons through the electron transport chain. As a result more free radicals are created at cytochromes 1 and 2. The combination of higher levels of ATP and free radicals sends a specific signal to the nucleus to upregulate genes for antioxidant synthesis, allowing the mitochondria to maintain its high metabolism without accelerating cell aging.

When a photosensitizer is present it sets off the series of possible reactions seen above. First, it absorbs light raising its energy to an excited singlet state. Then that energy can be dispersed in several different ways.

Often that energy will be re-released immediately in the form of light or heat and the molecule will drop back to its default state (this is how retinal in photoreceptors works). In other cases the molecule with make a jump from the singlet state to a triplet state. 

In the triplet state it is able to hold the energy for longer, and sometimes this results in slower energy release as light (called phosphorescence, similar to fluorescence). In other cases, its electrons are shifted into nearby oxygen causing it to be converted into singlet oxygen or producing free radicals.

As a result, in many cases photosensitizers being activated creates singlet oxygen and free radicals. The more reactive singlet oxygen can also result in easier formation of free radical inducing factors like iron oxide, so this pathways can also lead to some additional damage.

Let's look at a few examples of this. As I mentioned in my lecture on seasonal eating, both cytochrome 1 and 2 act as chromophores, for UV light and blue light respectively. As a result when these light spectrums are present they generate ROS and singlet oxygen through the excitation of the electrons they contain, causing them to react with nearby oxygen, water, etc. 

The electron transport chain will still generate some ROS in general via random electron transfer, but light tunes this process in different ways depending on the spectrum. Thankfully in sunlight the infrared stimulating cytochrome 4 cancels out the ROS increase from blue/UV light. In artificial light, which contains blue light without infrared, the ROS can become damaging.

Another example of a photosensitizer is lipofuscin, a protein aggregate which accumulates in cells as they age. Lipofuscin accumulation triggers more singlet oxygen generation in response to blue light (source). Lipofuscin also limits mitophagy and autophagy, causing damaged cells/mitochondria to accumulate, which has even worse effects when combined with excess singlet oxygen.

The inverse of this is seen with some protective plant compounds. Carotenoids are a prime example, and actually have the ability to convert excess singlet oxygen back into its triplet form, a process which is actually fueled by some of the same light spectrums which fuel singlet oxygen production in other pathways. 

This is why the eyes are loaded with carotenoids like lutein, to provide more resistance against singlet oxygen and protect the eyes from damage. Reducing singlet oxygen also shifts the ratio between singlet oxygen and different ROS used in signaling like superoxide, which increases the turnover of damaged mitochondria. 

This is also why it's important to cycle seasonal light exposure, with higher superoxide increasing mitochondria turnover with peak sunlight levels, and in winter climate thermogenesis increasing creation of new mitochondria. The increased intake of colorful plant compounds like carotenoids near the equator, where these winter climates are absent, also helps to further tune free radical signaling and clear singlet oxygen. 

These compounds are borderline essential for optimal health though, and they can also be gained in smaller amounts from animal products like fish, eggs, etc, during winter months. A wide range of other plant compounds such as flavonoids or quinones can have similar impacts singlet oxygen, so getting a broad range of phytochemicals is ideal. Ancient cultures knew this intuitively and would consume herbal medicines and foods that are extremely dense in these compounds throughout their lives for good health.