Fueling the Body's Power House

Review of Cell Structure and Function

    If you’ve studied biology or life science, you may remember the analogy that cells of living organisms are like factories. All living organisms (plants, animals, fungi, even bacteria) are made up of one or more cells. The cell is the basic unit of life. Inside cells, there are structures called organelles. Each of these organelles have specific jobs. Like different sections of a factory, they work together to keep the body alive and functioning. Much like a factory, cells use materials and produce products for survival.

    If a cell were a factory, the nucleus would be the headquarters, the cell membrane would be the guarded gate around the factory, the cytoplasm would be the factory floor where products are produced and shipped, the endoplasmic reticulum would be quality control, and the mighty mitochondria would be the power house, providing energy for all of the factory’s activities.

The Origin of Mitochondria

    The prevailing theory for how the mitochondria originated as the cell’s energy producer is the Endosymbiotic Hypothesis.

    Picture it... Earth... 2 billion or so years ago: Covered in a vast ocean, there were no plants, no animals; the only living organisms were unicellular bacteria and archaea. These earliest Earthlings were anaerobic, meaning they did not require oxygen to live. This adaptation to life was a necessity because atmospheric oxygen was scarce at that time. Although oxygen was being created by photosynthetic microorganisms, all of the oxygen was being used up by chemical reactions in the ocean, such as with dissolved iron, which formed massive rock deposits when oxidized. Once oxygen had saturated the oceans, it began accumulating in the atmosphere. Increases in atmospheric oxygen lead to the formation of the ozone layer, which would shield life on Earth from the ultraviolet rays of the sun. The increased atmospheric oxygen became a toxic poison to the anaerobic organisms and their numbers were decimated. However, some bacteria adapted to this new environment and learned to utilize the toxic poison to produce energy.  

    How did this happen? Well according to the Endosymbiotic Hypothesis, somewhere along the way, one simple prokaryote, a single-celled organism without a nucleus, engulfed another and they developed a symbiotic relationship, living together, happily ever after. The engulfed bacterium eventually became incorporated into the cytoplasm of the other bacterium and became an energy-producing organelle, a mitochondrion. Mitochondria enabled organisms to utilize oxygen for the production of adenosine triphosphate (ATP) through cellular respiration, which provided a considerable evolutionary advantage in the oxygen-rich atmosphere. The oxygen-rich atmosphere and protection from ultraviolet rays enabled these bacteria to evolve in complexity and gave rise to a new branch in the tree of life: the eukaryotes, or single-celled organisms with organelles and a nucleus.

    As eukaryotes evolved into multicellular organisms, animals, and eventually humans, mitochondria remained as the energy-producing organelles. This means that all of us have this ancient bacteria in our cells that produce energy for us in the form of ATP.

Mitochondrial DNA, Mutations, and Mitochondrial Etiology of Chronic Disease

    Because they originated from bacteria, mitochondria and bacteria have similarities in structure and function. They are similar in size, they are surrounded by one or more membranes, they replicate through binary fission, and they have their own DNA. Mitochondrial DNA, mtDNA, is separate from the DNA of the nucleus and it encodes the wiring diagram for the cell's power house. While nuclear DNA is inherited from both parents (half from the mother and half from the father), mtDNA is inherited only from the mother. It cannot recombine, or mix, with other genes. Because mitochondria replicate through binary fission, a method of asexual reproduction, the two resultant cells are identical. The only way for mtDNA to change is through sequential mutation. 

    Sometimes mtDNA mutates due to errors in replication or unrepaired damage. Mutations primarily occur due to oxidative stress. Oxygen is essential for energy production, but dangerous when not totally controlled. Under normal physiologic conditions, Reactive Cxygen Species (ROS) act as messengers and regulate communication between cells. Free radicals are generated in these normal metabolic processes. Free radicals are electrically uncharged atoms with an unpaired valence electron. Unpaired electrons make atoms unstable because the electron wants to pair up with another electron, so it goes looking for other electrons and becomes highly reactive. Other sources of free radicals include absorption of extreme energy sources (e.g. ultraviolet light, radiation), enzymatic metabolism of exogenous chemicals or drugs, intracellular reactions of transition metals (e.g. iron, copper) and nitric oxide (NO). Pathological effects of cellular damage from free radicals include disruption of the plasma membrane, protein destruction, and DNA mutation. The body has a protective antioxidant system to remove free radicals; however, excess ROS can overwhelm this system. When damages go unrepaired, mutations in mtDNA may occur. These mutations in mtDNA can end up depriving the cell of ATP. 

    Medical science has come a long way in its understanding of the nucleic genetic influence on disease; however, the nucleic genome by itself does not give us all of the answers about what causes chronic and age-related disease. The nucleus cannot do anything without energy. The mitochondria encode the key genes that determine how energy is apportioned and they communicate to the nucleus. Mitochondria are the environmental sensors. When there's an environmental challenge, mitochondria send metabolic signals to the nucleus, causing changes in nucleic expression in order to reestablish homeostasis and health. This process allowed humans to adapt to new environments by varying energy output and heat production according to climate. However, if an environmental challenge is too great or if there is a defect in the genes, the challenge cannot be corrected, causing deprivation of energy and decreased cellular function. When cells are deprived of energy, there is decreased cellular function, leading to disease and an acceleration of the aging process.

    When we look at various chronic disease processes at the molecular and cellular level, they look surprisingly similar. Nutrient deficiencies and exposure to various environmental and cellular toxins contribute to an inflammatory process and cause mitochondrial dysfunction, leading to decreased energy to the cells. Mitochondria are especially susceptible to nutrient deficiencies, environmental toxins, and oxidative stress. Mitochondria require a continuous supply of raw materials for production of ATP. If these materials aren’t available, they can sometimes be scavenged from another source, even if they’re not exactly the right materials. The result may be an end product that is not quite right. If materials cannot be found, production may stop. When the cell is working optimally, waste products are eliminated; however, nutrient deficiencies may cause this system to be less efficient, causing waste products to build up and damage mtDNA.

    Dr. Douglas C. Wallace, Professor of Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania and Director of the Center for Mitochondrial and Epigenomic Medicine (CMEM) at the Children's Hospital of Philadelphia Research Institute, discusses research in the field of human mitochondrial genetics and the mitochondria's relationship to specific disease etiologies in this lecture at a UCLA CTSI seminar in 2017:

    If we treat all people at the molecular and cellular levels to address the broad problems of inflammation and mitochondrial dysfunction, we will see improvement in health. Optimizing nutrient status to limit and provide protection from oxidative stress is something we can do to improve mitochondrial function. Researchers have found that a few key nutrients can improve mitochondrial function. Although many nutrients are necessary for ATP production, the most essential nutrients are listed below [1]:

• Thiamine (Vitamin B1)
• Riboflavin (Vitamin B2)
• Niacin (Vitamin B3)
• Coenzyme Q10
• Carnitine
• Lipoate
• Iron
• Magnesium
• Manganese
• Glutathione

I don't make this stuff up:

1. Pizzorno J. (2014). Mitochondria-Fundamental to Life and Health. Integrative medicine (Encinitas, Calif.), 13(2), 8–15.

2. Wallace D. C. (2013). A mitochondrial bioenergetic etiology of disease. The Journal of clinical investigation, 123(4), 1405–1412. https://doi.org/10.1172/JCI61398