In functional integrative medicine, as we work to understand the root causes of chronic disease, we often encounter a subset of patients who do not seem to respond to typical lifestyle and nutritional support therapies. While the role of mitochondria in cellular energy production and especially within our immune system is well-established, modern research has uncovered an important cellular signaling system in health and disease—the cell danger response, or CDR.

What is the Cell Danger Response?

Robert Naviaux, MD, PhD is the foremost researcher on this topic. The CDR is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that could harm the cell.1 Abnormal persistence of the CDR can ultimately lead to organ dysfunction and result in chronic disease. The mediation of this CDR is through purinergic signaling, or the signaling of molecules such as adenosine triphosphate (ATP). Within cells, ATP is a critical energy source, but extracellular ATP or eATP acts as a danger signal to the cell and activates the CDR, which initiates additional changes in metabolism and mitochondrial function.1

Mitochondria and the Cell Danger Response

Once the CDR has been activated, there are three key checkpoints and stages of the healing cycle that must progress before healing can occur. If the CDR gets stuck at any of these stages, chronic disease will be the result. CDR1 is the stage of containment and innate immunity (inflammation) and is metabolically characterized by glycolysis and high levels of eATP.2 During this stage, mitochondria predominate with the rounder M1 morphology, replacing mitochondrial membrane lipids with more saturated fatty acids, resulting in stiffer membranes and poorer energy production.2

After progressing through the CP1 checkpoint, the cell enters the CDR2 phase, which is characterized by cellular proliferation, aerobic glycolysis, and moderate levels of eATP. At this point, undifferentiated M0 mitochondria are recruited from neighboring stem cells. After the CP2 checkpoint, the cell enters CDR3, which is characterized by autonomous oxidative phosphorylation and cellular differentiation and remodeling. At this point, eATP is low and M2 mitochondria (which have a more filamentous morphology) increase with an anti-inflammatory effect and more efficient energy production.2 Finally, progression through the CP3 checkpoint indicates cellular safety signaling and health, with balanced glycolysis, aerobic glycolysis and oxidative phosphorylation. 2,3

The Bottom Line

The United States now spends $2.8 trillion annually on medical care for children and adults with chronic conditions.3 The collective exposure to thousands of natural and man-made chemicals keeps cells in a cell danger response, impeding progression to healing.3 To better support health, there are several tools and nutrients that can be used to help restore cellular and mitochondrial membrane function. Supportive lifestyle approaches include adequate sleep, exercise, fasting and caloric restriction.5 Nutrients that support the mitochondria include L-carnitine, alpha lipoic acid and CoQ10.5 Other promising tools include membrane lipid replacement, which replenishes cell membranes with omega-3 fatty acids, and phospholipids like phosphatidylcholine that improve membrane fluidity and function.4,5


Video Resources:
  1. [Watch] The Secret Life of Our Mitochondria, Robert K. Naviaux, MD, PhD

  2. [Watch] Powering the Healing Cycle, Robert K. Naviaux, MD, PhD

Helping physicians find patients who they can best help

Head shot of Kareem Kandil, MD, ND


Dr. Kareem Kandil is the Immune Foundations Clinical Brand Manager at Lifestyle Matrix Resource Center. Upon graduating from medical school at Ross University School of Medicine, Dr. Kandil went on to do an observership in integrative medicine and then pursued his Doctorate of Naturopathic Medicine (ND) at National University of Health Sciences in Lombard, IL.


  1. Naviaux, R. K. (2014). Metabolic features of the cell danger response. In Mitochondrion (Vol. 16, pp. 7–17). Elsevier BV.
  2. Naviaux, R. K. (2019). Metabolic features and regulation of the healing cycle—A new model for chronic disease pathogenesis and treatment. In Mitochondrion (Vol. 46, pp. 278–297). Elsevier BV.
  3. Naviaux, R. K. (2020). Perspective: Cell danger response Biology—The new science that connects environmental health with mitochondria and the rising tide of chronic illness. In Mitochondrion (Vol. 51, pp. 40–45). Elsevier BV.
  4. Nicolson, G. L., & Ash, M. E. (2014). Lipid Replacement Therapy: A natural medicine approach to replacing damaged lipids in cellular membranes and organelles and restoring function. In Biochimica et Biophysica Acta (BBA) - Biomembranes (Vol. 1838, Issue 6, pp. 1657–1679). Elsevier BV.
  5. Nicolson, G. L., & Ash, M. E. (2017). Membrane Lipid Replacement for chronic illnesses, aging and cancer using oral glycerolphospholipid formulations with fructooligosaccharides to restore phospholipid function in cellular membranes, organelles, cells and tissues. In Biochimica et Biophysica Acta (BBA) - Biomembranes (Vol. 1859, Issue 9, pp. 1704–1724). Elsevier BV.