Is There a Connection Between Mitochondrial Disease and Adrenal Fatigue?

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Often told they have adrenal fatigue, to patients with mitochondrial disease, it sounds like one more health issue standing between them and the life they dream of. However, exciting new research shines light on the direct link between altered mitochondria and effects on stress response.

Understanding how the body coordinates multiple body systems in response to a stressor clarifies why poor mitochondrial health sets the stage for health issues.

Activating a response requires abundant energy and signaling from the mitochondria. Excessive long-term stress can also damage mitochondria and lead to disease in those who are vulnerable. Since everyone has both mitochondria and stress, one needn’t have mitochondrial disease to benefit from understanding the relationship.

What Determines Your Ability to Handle Stress?

New research demonstrates the critical role stress plays in health conditions. The important thing is not the stressor, rather how the mind and body perceive it. How an individual responds and where they’re most vulnerable is dependent upon the combination of a number of criteria, including the following:

  • Mitochondrial health –oxidative stress and mitochondrial DNA
  • Genetics – alterations in neurotransmitters are passed on generationally
  • Environment – stress from physical and psychological factors
  • Coping mechanisms – inability to handle disturbances
  • Childhood trauma – including divorce which increases anxiety as an adult

The Body’s Stress Response

The adaptive design of human stress response has been key to ensuring our survival. Historically, when a stressful event occurred, the body activated an all-system response. Once the situation passed, everything resumed to normal.

In the modern world, stress on the body is chronically activated affecting everything from our sleep patterns, blood sugar regulation, immune response (which is inflammatory), thyroid function, fertility and mitochondrial health. The physiology that ensured our survival is now predisposing us to disease, since the system wasn’t designed for chronic activation. For those with mitochondrial disease, signaling is off-kilter from the start and the consequences are evident. For a better understanding, it’s important to first look at the normal signaling process:

  1. Stress hormones are released to make glucose (blood sugar) available for immediate use.
  2. Energy is distributed in a new pattern: directed towards brain and muscles.
  3. Immune system is activated, releasing inflammatory cytokines.

The stress response is a carefully modulated system that includes hormones (i.e. cortisol), blood sugar (glucose and insulin), nervous system, cardiovascular and immune responses. The HPA –axis has a primary role in regulating these systems and ensuring homeostasis.

To execute a response, extra energy is made available to fuel essential responses (i.e. increased blood pressure and blood sugar) and withdrawn from systems that aren’t essential for immediate survival (i.e. reproduction).

The Effects of Altered Mitochondria and Stress

All this activity requires chemical signaling and lots of energy (ATP) from the mitochondria. Clearly if problems exist in producing ATP, the systems will struggle to perform. That is exactly what occurs in mitochondrial patients.

When mitochondria have genetic alterations present, corresponding alterations occur in varying aspects of the stress response. How an individual experiences this occurrence depends in part on mitochondrial DNA. This topic is precisely what researchers at the Center for Metabolic and Epigenomic Medicine (CMEM) in Philadelphia studied.

The work at CMEM further established mitochondria as being stress response modulators. The findings have significant implications for mitochondrial disease as well as disease processes in general. Researchers modified various genes in the mitochondrial DNA of mice. Some genes were altered and others were deleted altogether. Mice were then exposed to stress and their biochemical responses were compared. Parameters included the effects on the heart, hormones, insulin, glucose levels, etc. An altered gene translated to an altered response, which was generally exaggerated compared to untouched mice. It was also found that an altered gene alone could directly cause a stressed response, even without a stressor present. For instance, stress causes a surge of cortisol to be released, which increases blood sugar levels, a condition known as “hyperglycemia”. In certain mutated mice, this effect occurred solely from having an altered gene.

Other findings showed:

  • A distinct stress response signature for each of the altered genes.
  • A distinct amino acid signature was present with altered gene patterns.

Overall the brain and nervous system are especially vulnerable to altered mitochondria, which was further illustrated in the CMEM study. Considering the brain uses 20% of the body’s energy while only accounting for 2% of the body’s mass, increased vulnerability makes sense. Ultimately the effects of mitochondrial dysfunction can lead to altered brain function and mental health.

The Mitochondrial Patient: Symptoms

The perception of stress along with the response pattern is all evidenced as being altered with the genetic alterations associated with mitochondrial disease. In everyday terms the responses to impaired stress are unwanted symptoms resulting from the body redistributing its energetic resources including: hormones, blood supply, blood sugar, and inflammatory cytokines. The following are some of the many ways the situation manifests in these patients:

  • Cytokines: chemical messengers of the immune response, which can cause pain and fatigue
  • Poor blood sugar control
  • Poor immunity causing increased susceptibility to infections
  • Neurological issues including heightened sensitivities to environmental stimulus
  • Heart palpitations
  • Anxiety and depression
  • Difficulty recovering from physical activity

What’s The Answer?

Supporting mitochondria and the HPA- axis can help turn the tide. While minimizing exposure to stressors, including dietary, emotional, psychological and physical, one also reduces oxidative stress, which is damaging to mitochondria. Here are some recommendations:

  • Avoid processed foods and sugar
  • Increase leafy greens, sulfur-rich vegetables and omega-3s
  • Eat a rainbow of colored produce, ideally organic
  • Supportive relationships
  • Learn better coping skills – check out our stress-reducing tips here
  • Sleep
  • Yoga, meditation, exercise (without going overboard)
  • Adaptogenic herbs, i.e. rhodiola, & ashwagandha
  • Magnesium, Alpha-lipoic acid, CoQ10, l-carnitine, NAC, vitamins C & D, and B12 (we recommend HoltraCeuticals for high-quality vitamins and supplements)

Much more research is needed to fully understand the implications of the topics discussed. The good news is advances in mitochondrial medicine are happening at a rapid pace. Nonetheless, answers can’t come soon enough for those struggling with these issues on a daily basis.


1. Kresser, C. Adrenal Fatigue or HPA Axis Dysregulation? The Kresser Institute.

2. Picard M. McManus, M. Gray J. Nasca, C. et. al. Mitochondrial Functions Modulate Neuroendocrine, Metabolic, Inflammatory, and Transcriptional Responses to Acute Psychological Stress. PNAS, 2015 112(48) E6614-E6623;published ahead of print Nov. 16, 2015.

3. Shames, R. L. Nutritional Management of Stress-Induced Dysfunction. ANSR- Appl Nutr Sci Rep. 2003 Nov; 576: 1- 7.

4. Shaughnessy, D. McAllister, K. Worth, L. Haugen, A. Mitochondria, Energetics, Epigenetics, and Cellular Responses to Stress. Environ Health Perspect. 2014 Dec; 122(12): 1271-1278.

5. Schneiderman, N. Ironson, G. Siegel, S. Stress and Health: Pyschological, Behavioral, and Biological Determinants. Annu Rev Clin Psychol. 2005; 1: 607-628.

6. Sivitz, W. Yorek, M. Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities. Antiox Redox Signal. 2010 Feb 15; 12(4): 537-577.

About Holtorf Medical Group

The Holtorf Medical Group specializes in optimizing quality of life and being medical detectives to uncover the underlying cause of symptoms, rather than just prescribing medications to cover-up the symptoms. We are experts in natural, prescription bioidentical hormone replacement and optimization, complex endocrine dysfunction, fibromyalgia, chronic fatigue syndrome and Lyme disease.

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