How This Tag Team Produces Neuroprotective Effects
Mitochondria are known as the powerhouses of cells.
These small, bean-shaped organelles float freely inside almost every cell in our body, except for red blood cells which contain no mitochondria.
The number of mitochondria in an individual cell can vary greatly depending on the tissue type. For example, muscle cells need a lot of energy so they have loads of mitochondria, while skin cells don’t need as many.
One of their most important roles is to act like the cell’s digestive system by taking in biochemical energy from nutrients and breaking them down to create energy rich molecules – hence the powerhouse description. This biochemical process, known as cellular respiration, starts by oxidizing high-energy molecules – such as sugars (glucose) – and eventually converts them into water and carbon dioxide. The breaking down of these molecules release a form of energy, called adenosine triphosphate (ATP), which the cell can then use like a battery.
Of course, that isn’t all that mitochondria can do. They’re involved in many other non-ATP-related functions including major metabolic pathways used by a cell to build, break down, and recycle its molecular building blocks.
Autophagy is the natural, regulated, destructive mechanism of the cell that disassembles unnecessary or dysfunctional components. It allows the orderly degradation and recycling of cellular components. When a cell is damaged though oxidative stress, this function removes the faulty components and replaces them with new, better-working parts.
Apoptosis, on the other hand, is known as programmed cell death. If cells are no longer needed or if they’ve been damaged beyond repair, they commit suicide by activating an intracellular death program. This self destructive process is a necessary way to clear the system of cells that can’t be saved. By being involved in these processes – cell survival and/or death – mitochondria help determine the fate of cells and can influence homeostasis in the body.
Some other functions include:
- Signaling through mitochondrial reactive oxygen species (ROS)
- Regulation of the membrane potential
- Regulation of cellular metabolism
- Certain heme synthesis reactions
- Steroid synthesis
- Hormonal signaling
But what’s interesting is that scientists now believe that cannabinoids and the endocannabinoid system (ECS) could play a major role in all of these important biological functions. You see, cannabinoid receptors are found on mitochondria membranes and studies have shown that these CB receptors have a hand in regulating biological processes via modulation of mitochondrial energy metabolism.
Here we outline some of the latest discoveries on how the ECS and cannabinoids like CBD work together with mitochondria to enhance their function and restore physiological balance in the body.
CBD Targets Mitochondria to Regulate Intracellular Ca2+ Levels For Neuroprotection
One of the major biological functions of mitochondria besides energy conversion is its role in controlling the concentration of calcium (Ca2+) ions within the cell.
You see, calcium handling by mitochondria is a key feature in cell life. It’s involved in energy production for cell activity by acting as a key regulator for ATP, in buffering and shaping cytosolic calcium levels (to control intracellular Ca2+ signaling, cell metabolism, and cell survival), and also in determining cell fate by triggering or preventing apoptosis (programmed cell death).
Even subtle mitochondrial deficits can have negative effects that will ultimately cause the body to degenerate.
Mitochondrial dysfunction has been linked to energy deficiencies which are also associated with aging and age-related disorders like Alzheimer’s disease. Mitochondria also determine cellular survival by the generation of reactive oxygen species (ROS).
ROS are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis. However, during times of oxidative stress, ROS levels can increase dramatically and result in significant damage to cellular proteins, lipids and DNA. Elevated ROS levels and cellular damage are linked to many issues including cognitive dysfunction, age-related disorders, and cancer.
Therefore, identification of agents that can restore normal mitochondrial function is highly desirable.
But while both mitochondria and the mechanisms involved in the control of calcium homeostasis have been extensively studied, research is finding that cannabinoids and the ECS could be a major factor in regulating calcium levels in cells.
In a 2009 study published in the Journal of Neuroscience, researchers characterized the mechanisms by which CBD regulates Ca2+ homeostasis and mediates neuroprotection.
Using imaging studies of brain tissue cultures, they found that depending on the excitability of the cells, CBD was able to mediate Ca2+ regulation. Under normal physiological conditions, CBD had minimal effects on mitochondrial calcium mobilization, but while under conditions of high extracellular K+ it significantly reduced Ca2+ concentration in the cytosol (the liquid found inside cells).
What’s interesting is that CBD doesn’t activate the CB1 receptors on mitochondria. Instead, the researchers were able to demonstrate that CBD binds to and modulates the activity of the mitochondrial sodium-calcium exchanger (Na+/Ca2+ exchanger or NCX) which is a protein that acts as a channel for cells to improve intracellular Ca2+ homeostasis. This mechanism of action explains why they found CBD to be neuroprotective against mitochondrial toxins and cell death brought on by hydrogen peroxide and oligomycin.
The authors concluded that, “under pathological conditions involving mitochondrial dysfunction and Ca2+ dysregulation, CBD may prove beneficial in preventing apoptotic signaling (which causes a cell to self-destruct in a programmed way) via a restoration of Ca2+ homeostasis.”
In another study published in 2014 in Molecular Neurobiology, researchers studied the effects of CBD on rats with brain iron overload. Brain iron accumulation has been implicated in the pathogenesis of neurodegenerative diseases, including Parkinson’s and Alzheimer’s, and has been related to cognitive deficits in animals and human subjects.
A lack of a synaptic energy supply has been linked to neurodegenerative diseases – hence the key role that mitochondria play in neural cells and maintaining functional circuits. It has also been shown that brains of patients suffering from neurodegenerative diseases have increased expression of apoptosis related proteins and specific DNA fragmentation.
In the study, the researchers were able to demonstrate that CBD played a role in restoring the damage caused by iron loading in rats by bringing the levels of DNM1L, caspase 3, and synaptophysin, down to normal levels. DNM1L, caspase 3, and synaptophysin are proteins that are involved in mitochondrial fusion and fission and also apoptosis. Elevated levels of these proteins are associated with synaptic loss and apoptotic cell death. They concluded that, “CBD should be considered as a potential molecule with memory-rescuing and neuroprotective properties to be used in the treatment of cognitive deficits observed in neurodegenerative disorders.”
In part 2 of our article on CBD and Mitochondria, we dive into how the ECS and cannabinoids can work together with mitochondria to produce cardioprotective and anti-cancer effects as well. Stay tuned.
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