Redox Signaling — Smoke Signals from Metabolic Fires



As we sit inside our cozy homes, in front of the fireplace that brings us warmth and energy, we feel the benefits and all seems well. What happens if smoke from the fire started billowing out into the room? We are immediately alerted, smoke alarms go off, we are moved to immediate action. We realize that besides providing energy, fires can be dangerous. Fire produces smoke, free radicals, carbon monoxide, sparks and ash, fires can get out of control. In order to harness the ample benefits of fire, we have made special places in our homes where the fires can be controlled. We have devices that control the fire, harvest the energy, and alert us if the smoke builds up. This scenario provides us a great analogy of what is happening inside our trillions of cells. Inside every one of our cells, fuels are delivered, like oils and gasoline (fatty acids and sugars), that burn with the provided oxygen inside an average of 200 controlled furnaces (called mitochondria) in every cell, this fire produces smoke (ROS) that is eliminated by scrubbers (antioxidants) and detected by smoke detectors (thioredoxin semaphores, Nf-kappaB). All of these devices must be in place inside our cells to harness the energy of these metabolic fires.

At the junctions inside the cells where the oxygen pathways and fuel pathways merge, the fire of life provides energy. Even on a molecular level, nothing happens without energy. The major reason that we search for food and take in oxygen is to provide the fuel molecules and oxygen molecules maintain these vital fires of life inside our cells. Within this fire of life, the universal energy molecule, ATP, is forged. ATP powers all of the molecular machines, players, instruments, everything that requires energy in our cells. Every time you blink an eye, think a thought, twitch a muscle or feel a breeze, trillions of ATP molecules are spent to fuel the action. If the fire of life were to go out, in seconds the cell would run out of its supply of ATP energy molecules and the concert of life in the cell would quickly come to an end. There is nothing more important to a cell than to keep these fires burning.

The “smoke” that comes out of these cellular fires, reactive oxygen species (ROS), composed mostly of superoxide free radicals (O2*-) and hydrogen peroxide (H2O2), increases when the fires of life flare up inside the mitochondrial furnaces. These ROS (smoke) molecules affect the semaphore molecules (smoke detectors) that, in turn, change “color” and redirect molecules along the pathways. In other words, these smoke detectors are intelligent and are wired to make changes inside the cell. This is at the essence of redox signaling. The ROS superoxide free radicals (O2*-) and hydrogen peroxide molecules (H2O2), just like smoke, are highly energetic and reactive, and can also damage certain sensitive structures in the cell (like the DNA). Thus plant and animal cells have adapted to produce various types of antioxidant enzymes (smoke scrubbers), such as glutathione and SOD that can eliminate ROS “smoke” and keep it out of sensitive areas. As might be expected, these antioxidant enzymes are tightly regulated and controlled by redox signaling networks. For example, too much hydrogen peroxide in the cell will activate the redox signaling semaphores along pathways that turn down the metabolic fires and increase the production of antioxidants (smoke scrubbers) needed to eliminate the ROS (smoke).

Many of the redox regulatory processes are aimed at maintaining proper homeostatic balance of redox potentials in all the fluids in the various parts of the cells and tissues. Shifts in the redox potential (smoke signals) of vital fluids in and around the cells will generally activate redox signaling pathways that are designed to ultimately return the redox state to “normal” again. In the past decade, we have learned that it is dangerous to try to force the elimination of all superoxide free radicals or hydrogen peroxide in our body. In fact, the body will try to counterbalance any efforts to change the established natural balance by producing more of the lacking species to compensate. In order to maintain life processes, we require well-balanced control of these types ROS in our body. There are a variety of redox signaling pathways that naturally maintain normal redox balances and potentials throughout all the fluids in our body. Without both the oxidants and the antioxidants inside these vital fluids, this homeostatic balance would quickly be destroyed, and we would surely die. ROS is an essential signaling molecule.

If we were to completely eliminate the smoke from the fires inside our cells, the smoke detector semaphores would not be activated when the fires flare up and get out of control. ROS smoke is required to make the whole system work. Without ROS smoke, the damage detection mechanisms are shut down. In the vast majority of cancer cells, for example, the redox signaling system has been shut down, the mitochondrial furnaces have been shut down, the redox detection semaphores (smoke detectors) are not able to work. Without the aid of this redox signaling system, these damaged cells cannot be effectively detected, repaired or destroyed; they become immortal and remain broken. Smoldering fires are not extinguished, damage is propagated. Life is threatened.

As we contemplate these concepts, we realize that life is preserved by those devices inside our cells that maintain proper redox balance. It creates that cozy space inside our cells, where all is well; the fires are burning at their proper level, the smoke is being handled and the energy efficiently harnessed. When fires flare up, smoke billows out, alarms go off, smoke detectors are activated that will push the genes that will bring it all back into control. That is one description of redox signaling.


Redox Pathways Interconnect the Body

These last few weeks, much has happened in the world of Redox Signaling. James Watson, who co-discovered the 3-D helical structure of DNA, has stepped forward with an article in the prestigious Lancet journal to champion this field of science, stating that he considers his work in this field to be his greatest accomplishment since DNA. You can type “Watson Redox ROS” into any search engine to explore this. The formal research on redox signaling has to do with how reactive oxygen species (ROS, examples: H2O2, O2*-,ClO-,etc.), reactive nitrogen species (RNS example: NO) and reactive sulfur species (RSS example: H2S) interact with the molecular semaphores in the vast ocean of fluids inside us. These molecular semaphores are proteins (like thioredoxin) that change conformation and state when they come into contact with these reactive molecules and redirect molecular traffic in our cells. Imagine the implications.
Amazing as these molecular processes of life inside our cells may seem to us, possibly even more amazing is that trillions of individual cells combine to form the complex tissues and organs that pump our blood, think our thoughts and move our muscles. The enormity and complexity of any one of these machines is mind-boggling. Take a moment and ponder the importance of the proper function the cells, with all of the molecular machinery inside them, to the vital functionality of the whole organism. These tiny molecular machines are all seemingly unaware of the crucial role they play in the big picture as they complete their tasks with incredible precision and speed. And yet they cannot be completely oblivious to everything that is happening even trillions of cells away. The tiny molecules that move our muscles, for example, must react to signals from our brain originating from relatively vast distances away, they are sensitive to these signals and know exactly what to do when they come. In fact, it would be wrong to say that all of these tiny molecular machines act independently of each other, even if they are separated from each other by truly astronomical distances on the atomic scale. In a very real sense, they all are connected by the signals that they send to each other.
Single-cell organisms do not have to be connected to anything beyond what is happening in their immediate environment. Signals from the outside mostly help the single-cell organism to find food or light and help it avoid dangers. In a sense, single-cell organisms are selfish, their biological mechanisms are tuned mostly to their own individual survival, their molecular machinery is focused on sustaining proper internal function and they do not need the complex, elaborate external messaging systems that exist in multi-cellular organisms. This gives single-cell organisms, like bacteria, a disadvantage when compared with multi-cellular organisms. We will see, later on, that our immune system is able to detect and kill bacteria with the help of a combination of reactive oxygen species (ROS) that rips apart bacteria and simultaneously activates redox signaling networks in and between our cells. Over hundreds of millions of years, bacteria and primitive single-cell organisms have not been able to adapt to dominate multi-cellular life. In principle, our immune system is universally effective.
It might be interesting to contemplate, for a moment, what the fundamental differences are between single-cell and multi-cellular organisms. Cooperation, almost by its definition, seems to be the key to success in multi-cellular organisms; cooperation that is mediated by the connections made between the cells. If we are working on the scale of the molecular machinery inside each of the individual cells, then being connected means that cells can send messages between each other that will alter the way these tiny molecular machines conduct business in each of the connected cells. It may even mean that individual cells can be asked to sacrifice themselves and shut down for the good of the whole organism. The individual cells are programmed to obey the directives that are sent through their connections. These connections become absolutely essential for the survival of the organism.
Suppose, for example, that a single cell in your body cuts off the connections it has to all the other cells. This rogue cell can no longer receive the messages and directives from the rest of your cells and starts to act in a way as to preserve its own survival, similar to a single-cell organism. It becomes a cancerous cell. If it is successful in its struggle to survive and duplicate itself, then the whole organism will eventually die. In a very real sense, it is the connections made between cells that allow them to cooperate and to fulfill their own appointed role. Through these connections, billions of your cells every day realize that they are damaged and are called upon to selflessly sacrifice themselves, to die and to be replaced by the division of neighboring healthy cells, in order to help preserve the health of the organism as a whole.
On the most fundamental level, the molecular machines in your cells react, shift and change based on the messages that come into them through the connections that exist between your cells. They all work to fulfill their appointed roles, precisely and faithfully. There are literally thousands of different types of messages that are sent between cells, both chemical and electrical, that influence the way these tiny molecular machines function. In a very real sense, all of the 50 to 100 trillion cells in your body are all intricately connected and unified to provide you with the precious gift of life that you now possess.


Orchestrating the Pathways of Life — Redox Signaling Semaphores

These first few posts are helpful to bring our minds into the framework that will allow us to understand what life looks like on the molecular scale, all with the end to help conceptualize what the signaling networks that define life and connect all of the molecular players might look like on the molecular scale inside our body. On the molecular scale, everything is immense; there are a trillion billion water molecules in just one small drop of water, almost an unfathomable amount; in reality even the smallest drop of water contains a vast ocean of water molecules, stretching off into infinity in all directions in the molecular perspective. Even a single cell in this perspective, contains an enormous pool of molecules surrounded by an undulating membrane containing “windows” and “doors” (receptors) that allow molecules to pass through from the outside to the inside of our cells. Each cell can be thought of as a submerged “house” that protects the processes of life taking place inside. The molecular materials and supplies that the cell needs comes in through selective “windows” and “doors” (oxygen, nutrients, building materials, etc.); very few molecules can “seep in” through the cracks.
The pushing and pulling action of the constantly jostling sea of water molecules mark the pathways that molecules follow as they navigate through this ocean of water molecules inside your body. As molecules travel through this sea of water molecules, it can be somewhat like watching a huge “pinball” game. The traveling molecules will be bounced, pushed and pulled along through an array of “bumpers” and “magnets” until they finally arrive at their destination. Every once in a while, there will be a “bumper” or “magnet” in this sea of molecules that will push or pull them in the desired direction. It is amazing how much control can be exerted over seemingly random processes by a few well-placed “bumpers” or “magnets” in this huge molecular pinball game of life. The “signal beacons” that mark the pathways are often well-placed molecules that simply help nudge the ocean travelers in the desired direction. The “windows”, “doors” and “mailboxes” outside and inside the cells are full of specialized “signaling beacon” molecules that are specially designed to attract or repel only specific kinds of molecules out of the sea of passing molecules, making for a well-marked and designated pathway for certain kinds of molecules. Due to the combined efforts of all these types of well-placed signaling beacon molecules, all the molecules of life are able to successfully navigate the pathways of life in the ocean inside us and arrive safely at their intended destinations, even over what might seem to be astronomical distances on the molecular scale. The true glory and intelligence of the cell lies in how it controls this molecular signaling beacons and the traffic they direct. Five Nobel prizes have been awarded in as many years for work in understanding cell signaling, the implications are incredible.
What are the factors that determine the action of these “signaling beacons” that guide the molecules of life along the myriad pathways traversing the ocean inside us? We find that the real factors that determine these pathways lead us to examine the details of what happens in the local molecular environment surrounding the signaling beacons that mark the pathways. And what happens in the local environment around these signaling beacons is intimately connected to what is happening in the sea of constantly moving water molecules, and islands of charged clusters, surrounding these signaling beacons. So if we want to know the answer, it all comes back around to what happens in the salt-water environment that transmits signals to the surrounding molecules. Again we realize that the critical clues to life are found in what happens in the world of the all-encompassing water molecules. So, how are signals transmitted through this sea of water molecules?
Changing the redox potential or pH in the neighborhood of a “signaling beacon” can change the nature of its signal and thus shift the associated pathway. For a simple analogy, think of a signaling beacon as a “semaphore” floating on a buoy in the middle of the ocean. Changing the redox potential in the water surrounding the signaling beacon can change the “color” of the semaphore, say from green to red. This change of state shifts the “traffic patterns” of the molecules that are directed by this signaling beacon and thus shifts the pathway of millions of the molecules traveling through our internal ocean. This kind of signaling is referred to as redox signaling, it changes the nature of the signaling beacons and redirects the molecular pathways through the ocean of life inside us. There are molecular pathways that control literally every aspect of our existence. Pathways in our brain allow us to store our memories, think our thoughts, feel our feelings, and be aware of everything happening in our body and environment; joining with pathways in our body that beat our heart, breath our air, move our muscles, digest our food, control our metabolism and process billions of signals from every part of our body. We have seen that these pathways allow us to move the molecular materials and supplies needed throughout all of our cell communities. These pathways allow us to deliver the messages between the molecular players in our cells, tissues, organs and systems needed to operate our genes, sustain and maintain cooperation and homeostatic balance between all of our trillions of cells throughout all of our cellular communities.
We have come to an understanding that these life-sustaining pathways must allow molecules and electrical fields to pass through the vast fluid ocean of life that exists inside, outside and between all of our cellular communities and that connects all of the molecular players inside them. Finally we have come to a realization that all of the molecular traffic traversing these pathways through this vast sea of life are controlled by signaling beacons, much like “semaphores”, that determine what happens to the molecular travelers at the trillions of critical junctions or intersections all along the various pathways. We know how insulin and glucagon modify the glucose pathways in the body, for example. We ponder the question “Who controls these signaling beacons?” and find that, beside philosophical considerations, many of these signaling beacons are controlled by signaling molecules that exist in the sea of water molecules that surround them. These signaling molecules modify the state of the various signaling beacons (semaphores) that direct traffic along the molecular pathways. We will consider a special set of these molecules, redox signaling molecules, that are the most fundamental of all of these signaling molecules, composed of the very molecules that form the vast ocean inside us. We have quite a journey ahead of us.