Chronic fatigue syndrome (ME/CFS) and other complex chronic illnesses might have a common thread. When cells sense a threat, which can range from an infection to stress, metabolism in the cell slows down and goes into preservation mode. Mitochondrial expert and researcher Robert Naviaux, MD, PhD, has termed this cell danger response (CDR). Precisely, the mitochondria in cells sense threats, making them the canary in the coal mine.
What are Mitochondria
Mitochondria are commonly known as the cell’s powerhouse because they produce energy for most physiological functions. Tissues with increased energy demands have a higher concentration of mitochondria per cell. On average, cells contain between 1000 and 2000 mitochondria per cell, but brain cells contain up to 2 million mitochondria. The energy currency that mitochondria create is ATP (adenosine triphosphate), the most expensive thing cells produce. ATP cannot be stored in the body and must be continuously produced.
Mitochondria Do More Than Produce Energy
Mitochondria do more than produce fuel for all systems to operate. They also sense information from the environment, allowing the mitochondria to adapt to change. This concept is termed mitochondrial information processing system, or MIPS.1 In MIPS, the mitochondria sense external and internal environmental changes. Then, mitochondria integrate the information and produce output signals to other cell structures to regulate physiology systemically. The MIPS functions like a human communication network to ensure physiological processes work efficiently and humans adapt to environmental changes.
Pathogenesis: An Outdated Model of Chronic Disease
Pathology is the study of disease states and attempts to identify the cause of the injury. This model works well with acute injuries and illnesses where healing is passive and does not require energy. These illnesses account for only 10% of diseases. However, in chronic diseases that account for the other 90%, there is a process of healing that requires energy. Dr. Naviuax has termed this salugenesis and describes the healing phase of recovery from chronic illness.2
“For a long time, we have focused on the things that have caused the illness. The path from disease and chronic illness back to health is a different path.” Robert Naviaux, MD, PhD
Essentially, pathogenesis is what causes the diseases, and salugenesis is what causes the healing. Salugenesis is what is required to heal from chronic illness.
Stages of Cell Danger Response
The mitochondria provide energy and resources that drive cell danger response and the phases of the healing cycle. The classic approach to understanding a disease is to discover what makes it unique. Dr. Naviaux’s team was interested in learning what chronic diseases had in common. They discovered that chronic illnesses resulted from failure to complete the healing cycle.
“Once the pathogenic trigger has been treated or removed, chronic disease persists because healing is incomplete.” Robert Naviaux, MD, PhD
In this model, each chronic illness results from abnormal persistence of the normal phase of the healing cycle. Treatments directed at the pathogenesis cannot heal the abnormal persistence of the normal healing phase. The cell danger response is divided into three types based on the primary function. Phase 1 is Inflammation; Phase 2 is Proliferation; Phase 3 is Differentiation.
Chronic diseases associated with the cell danger response and incomplete healing
- Autoinflammatory disorders
- Autism spectrum disorder (ASD)
- Alzheimer’s dementia
- Bipolar disorder
- Cancers and leukemias
- Chronic fatigue syndrome (ME/CFS)
- Chronic infections – Bartonella, Lyme disease, Epstein-Barr virus
- Fibromyalgia
- Generalized anxiety disorder
- Hashimotos thyroiditis
- Inflammatory bowel diseases (Crohn’s and ulcerative colitis)
- Long COVID
- Migraines
- Mold related illness
- Multiple sclerosis
- Neuropathic pain syndromes
- Obsessive-compulsive disorder (OCD)
- PANS/PANDAS
- Parkinson’s disease
- Post-treatment Lyme disease
- Postural orthostatic tachycardia syndrome (POTS)
- Psoriasis
- Rheumatoid arthritis
- Traumatic brain injury (TBI)
All of these conditions – and more – have significantly increased in the past five decades. There has also been an increase in chronic diseases in pets, including cancer, leukemia, autoimmune conditions, allergies, thyroid disease, arthritis, and heart and kidney disease. This rise in chronic conditions in humans and animals would point to environmental causes.
The Rising Tide of Environmental Chemicals
In the past 50 years, there has been an increase in manufactured chemicals released into the environment. Dr. Naviaux and other researchers conducted a study between 2002 and 2020 to determine the increase in environmental chemicals.3 They collected plankton samples from the North Pacific Ocean and performed a comprehensive laboratory analysis. They found phthalates, plasticizers, persistent organic pollutants (POPs), pesticides, pharmaceuticals, and personal care products in the plankton. The toxicity in the plankton is a bioaccumulation of chemicals that humans are exposed to daily. Similar to a drop of water in an ocean, a drop of blood from a human provides insight into toxins in health and disease.
Mitochondria are the Canary in the Coal Mine
Because mitochondria sense threat or injury and send signals to other cells that there is danger, they must reprogram to move through the healing cycle. Different mitochondria perform different roles – some fight infections, others learn, and some help heal from injury. When complete healing occurs, the mitochondrial network is reconnected. However, if the mitochondrial network is blocked, a repeating loop keeps people stuck in chronic illness.
“Any cell that has mitochondria that can’t change their function is either diseased, dead, or soon will be.” Robert Naviaux, MD, PhD
ATP Release From Cells Signals Danger
The energy currency of cells, ATP, is released from cells under stress. The greater the stress, the greater the release of ATP. Extracellular ATP is the critical regulator of cell danger response. Damaged cell membranes allow the release of ATP through channels. Then, more channels open and release other compounds, including inflammatory cytokines. Dr. Naviaux refers to this as the ripple effect.
Oxidative stress from chemicals, toxins, infections, and more contribute to cell membrane damage. One approach to healing the cell danger response contributing to chronic illnesses is to repair damaged cell membranes with phospholipids. I have found this approach effective in my practice.
Mitochondrial Function vs. Dysfunction
Mitochondria provide hundreds of functions. Mitochondria are constantly recalibrating their function to meet the needs of local signals. Therefore, normal function depends on requirements at different times and locations. For mitochondria to heal after damage or stress, they must change their function.4
Stages of Mitochondrial Repair
The mitochondria go through various stages of healing. Healing is a process that occurs in a programmed sequence of functional states. The M2 stage refers to health; M1 is the proinflammatory stage; M0 is a proliferative stage. Once injury or damage occurs, mitochondria move from M2 to M1, the first stage of cell danger response (CDR1). Mitochondrial repair transitions from M1 to M0 in the cell danger response 2 (CDR2). Eventually, the goal is for mitochondria to heal and return to M2.
The stages of mitochondrial healing and cell danger response can be confusing for people without a medical or scientific background. What is essential to understand is that mitochondria go through a repair process that correlates with the phases of the cell danger response.
The Hit and Run Exposure
Sometimes, a person is exposed to a virus, bacteria, or toxin, and then that pathogen or toxin is cleared. The initial insult is no longer present, which is likened to a hit and run.” Healing is complete if the damage or injury is repaired within six months. Energy is required to heal if mitochondria do not heal within six months of an injury or stress. The damage or injury persists because cellular signals inform mitochondria that danger is still present and healing is incomplete. Interestingly, the vagus nerve tells the brain that danger is gone.
Three Hit Model of Chronic Illness
It is common for people with chronic illness to have experienced multiple “insults” over the years before they become sick. A person may have had Epstein-Barr virus in college, a head injury in their 20s, and then exposed to mold later in life. Symptoms develop after a tipping point, and the most recent insult is often blamed as the cause. I frequently see this with Long COVID.
Over 90% of chronic illnesses have multiple causes. Chronic disease can develop if there is significant severity or duration of one exposure, but there are typically two additional “hits.” Dr. Naviuax references the Developmental Origins of Health and Disease (DOHaD) model, which indicates a genetic and environmental predisposition to disease.5 There is a period before symptoms begin when someone is exposed to environmental exposures that trigger the cell danger response. Once the perfect storm of events occurs, symptoms develop. Eventually, more minor triggers produce a more significant response, contributing to the progression and persistence of chronic illness.
Cell Danger Response as a Cause of Chronic Illness
The incidence of chronic illnesses has risen significantly in the last fifty years. Over 90% of diseases people suffer from are chronic and create a significant impact on their quality of life. Dr. Naviaux’s model of cell danger response and how it contributes to incomplete healing in chronic disease provides a valuable framework for recovering from these debilitating conditions. Focusing on what caused the illness (pathogenesis) and not addressing healing (salugenesis) keeps people stuck in chronic disease and poor quality of life.
For example, this is seen in chronic Lyme disease. A person takes antibiotics for months or years, but their symptoms persist. The infection causes damage to cells and mitochondria and contributes to symptoms. The cause or trigger can be removed, but chronic disease persists because healing is incomplete. As Dr. Naviaux says about healing from chronic illness, “It is a whole body process that begins with mitochondria and the cell.”
