As mitochondrial dysfunction has become better recognized as a factor in disease, research is starting to focus on targeted treatment. Pathology in chronic disease is repeatedly showing damage to the mitochondria. Oxidative stress from the environment causes harm to the mtDNA, proteins, and lipids of the mitochondria leading to decreased energy production. If the mitochondria are less efficient, more free radicals are produced. This creates an ongoing cycle of progressive mitochondrial dysfunction.
Currently, there are no FDA-approved treatments for mitochondrial disease.1 Multiple pharmaceutical companies have ongoing early clinical trials targeting mitochondria. Upon looking at the mechanisms of these medicines, it is apparent they are targeting specific areas of mitochondrial dysfunction. Although energy production through the mitochondria involves multiple steps, these new medicines focus on one specific function.
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Targeting Oxidative Stress
One pharmaceutical medicine currently in clinical trials is MTP-131.1 The medicine is administered by IV or topically for ophthalmic use. The medicine MTP-131 was created to enter the mitochondria to reduce oxidative stress. The target of the medicine is a lipid called cardiolipin, which is critical for the inner mitochondrial cell membrane. The electron transport chain forms ATP exclusively on this inner membrane. If the membrane is altered causing damage to the cardiolipin, it releases cytochrome C into the cytosol of the cell beginning the process of apoptosis or self-destruction of the mitochondria. Often, an increase in free radicals causing oxidative stress will damage cardiolipin.
Targeting Activation of Nrf2
Activating the Nrf2-Keap 1 path-way begins a cascade of events that decrease inflammation and in-crease antioxidants. It initiates the production of the antioxidant enzymes catalase, superoxide dismutase, and glutathione peroxidase. Activation of Nrf2 also decreases the release of pro-inflammatory cytokines such as TNF-alpha. Mitochondrial efficiency and ATP production are also enhanced by this pathway. Targeting these cellular processes through the Nrf2 pathway has been an aim of pharmaceutical companies. A medicine called RTA 408 was developed to activate Nrf2. Clinical pre-phase 3 trials are currently underway.
Targeting Production of Glutathione
An investigational medicine called RP 103, a form of cysteamine, is in clinical trials.1 The molecule helps convert cystine into cysteine needed for formation of glutathione. Glutathione is the main antioxidant in cells. Cysteine is the rate-limiting amino acid in glutathione production. The medicine, by increasing levels of glutathione in the cells, is predicted to decrease oxidative stress damage to the mitochondria. Ongoing, open-label clinical trials are determining dosing levels, safety, and efficacy of the new medicine.
From an integrative perspective, it is more important to look at the underlying cause of the disease than the disease itself. Understanding the cellular mechanisms will help guide treatment more than a diagnosis. If there is mitochondrial dysfunction or oxidative stress, this needs to be treated. It does not matter if the disease is autism or Alzheimer's.
Targeting mitochondrial function involves supporting the mitochondrial membrane and supplementing the key nutrients needed for the formation of ATP.2,3 It also requires increasing antioxidant reserves in the body and decreasing oxidative stress. A comprehensive treatment approach requires supporting these functions simultaneously instead of one targeted treatment as in the pharmaceutical approach.
While the pharmaceutical companies are studying precursors for glutathione, liposomal glutathione is already available. Research on absorption has shown increases in glutathione levels with oral use.4 In addition, studies have shown clinical improvements in chronic disease with oral liposomal glutathione.5 Since glutathione is a critical antioxidant in the body, being able to safely and effectively restore levels is crucial for healing.
Many natural treatments have been shown to activate Nrf2 receptors. Curcumin, one of the active ingredients in turmeric, has multiple studies showing its ability to bind to the Nrf2 receptor and decrease pro-inflammatory cytokines.6-8 Resveratrol and EGCG in green and black tea extract have been also shown to be effective. Polyphenols, which include curcumin, resveratrol, and EGCG among others, all appear to be able to activate Nrf2 to increase antioxidants and decrease inflammation.9-13
A unique antioxidant, molecular hydrogen, has research supporting its ability to activate Nrf2 receptors also.14-16 In addition, molecular hydrogen has the capability to scavenge the dangerous hydroxy free radical.14-16 This free radical is highly reactive with cellular tissues resulting in more oxidative stress. Molecular hydrogen does not affect the free radicals needed for mitochondrial function or the activation of the antioxidant enzyme cascade including superoxide dismutase and catalase.14-16
Finally, awareness of the importance of mitochondria dysfunction and oxidative stress are being recognized for their role in chronic disease. Integrative medicine has been treating these issues for years. With an integrative and holistic mind set, we are well aware of the importance of a multi-modal approach. The pharmaceutical industry is trying to target the correct pathways but is still focusing on one part of a complex puzzle. Luckily, we have many natural treatments to implement simultaneously to promote recovery from chronic illness.
Dr. Debby Hamilton, MD, MPH, is a pediatrician with experience in primary care, integrative medicine, research, speaking, and writing. Her education includes an undergraduate degree from Wesleyan University followed by a medical degree from Chicago Medical School, where she graduated with honors. She is board-certified in pediatrics, physician nutrition, and integrated/holistic medicine (AIHM), and has a Master of Science degree in Public Health (MPH). Dr. Hamilton founded Holistic Pediatric Consulting in Colorado in 2005. Her practice focused on treating children with chronic diseases such as autism and ADHD and preconception counseling based on her book, Preventing Autism and ADHD: Controlling Risk Factors Before, During & After Pregnancy. Her book led to her collaboration in the writing of The Healthy Child Guide through the Neurological Health Foundation. She has also contributed chapters for Child Decoded: Unraveling Learning and Behavioral Disorders. In 2017, Dr. Hamilton joined Researched Nutritionals. Her focus is managing and expanding Researched Nutritional's clinical research on the efficacy of nutritional supplements, working on protocol development, and promoting the education of healthcare professionals.