Beyond the Mitochondria: Endoplasmic Reticulum Stress

ER stress

Mitochondrial interventions are the mainstay of many ME/CFS and fibromyalgia treatment protocols. Well known mitochondrial nutrients such as CoQ10, NADH, D-ribose, carnitine among others, likely make up your supplement drawer.

These nutrients function to relieve mitochondrial stress which is characterized by inadequate ATP production and oxidative stress. These all are valuable supports and provide mild relief for many patients. But why do some experience no relief with mitochondrial nutrients?

Could it be because mitochondrial damage is NOT the prime driver, but a consequence of something else?

Could it be that mitochondrial damage comes about as a consequence of damage to another key cellular organelle?

Enter the endoplasmic reticulum...

Inside the cell, the main function of the endoplasmic reticulum (ER) is to fold and transport proteins. Like a busy laundromat, the ER can only handle a finite amount of protein folding before it reaches capacity. If overloaded, the ER institutes a shutdown mechanism in an attempt for quality control. In a complex cascade of events, the ER begins to unfold proteins, halting new folding, and cleaning up misfolded proteins in an effort to get back on track.

If the machinery still can’t catch up with its duties, the alarms go off that signal the ultimate demise of the entire cell--apoptosis. Chronic ER stress is believed to be involved in a number of degenerative diseases including Parkinson’s, Alzheimer’s, ALS, cardiovascular disease, diabetes, bipolar disorder, cancer, autoimmunity, and others.

The link between ER and mitochondria

The ER and mitochondria are intimately linked; communicating via chemical crosstalk with cytokines and other signaling molecules. Chronic ER stress leads to the release of inflammatory cytokines that promote oxidative stress which in turn damages surrounding mitochondria. A proverbial house of cards is set into motion--cellular machinery collapse of both the ER and mitochondria.

Calcium Homeostasis

Another important function of the ER is in maintaining calcium balance by serving as a depot. With ER stress, calcium is released in abundance where it overwhelms other organelles and cells. An influx of calcium into mitochondria for example, destroys the mitochondrial scaffolding (cardiolipin and cytochrome C) which leads to mitochondrial death. Also, it is well known that calcium influx into neurons results in loss of normal neurotransmitter release, myelin repair, and neuronal plasticity.

Another unfortunate consequence of calcium imbalance from ER stress is the activation of NF-kB—the MAJOR inflammation regulator of the cell. Induction of NF-kB initiates a vicious cycle of inflammation, oxidative stress, and mitochondrial damage.

Viral Infections and ER Stress

In order to replicate, viruses require the ER to assemble viral proteins. As expected, this places undue stress on the ER. As mentioned above, with an increased demand for proteins the ER should normally commence quality control unfolding mechanisms. Instead, viruses manipulate the process and block key steps to ensure the takeover of the “cellular laundromat.”

The exact mechanisms in which viruses manipulate the ER are still unknown. From research with HSV, CMV, EBV, Hepatitis, and other viruses, it appears that certain classes of viruses use different strategies to hijack the ER.

ER Stress and the Immune System

A clear detriment of chronic viral infection and ER stress is the inability to properly fold proteins important for the innate immune response. Plasma cells, myeloid cells, and dendritic cells all require optimal ER functioning for proper development. All of these immune cells have been implicated in ME/CFS pathology.

Could the ER be a potential point to intervene in the chronic infections seen in ME/CFS?


ER dysfunction can occur due to:

  • Aberrant calcium homeostasis

  • Viral infections

  • Hyperglycemia, hyperlipidemia

  • Oxidative Stress

  • Xenobiotic exposure

Ways to Intervene

  • Reduce oxidative stress as much as possible through high antioxidant diet and nutrients.

  • Block calcium influx through known antagonists like NAC, magnesium, DHEA, vitamin D, and taurine


1  Cláudio N, Dalet A, Gatti E, Pierre P. (2013) Mapping the crossroads of immune activation and cellular stress response pathways. EMBO J. 32(9):1214-24.

2  Chaudhari N, et al. (2014) A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress. Front Cell Neurosci. 8:213.

3  Mostafalou S, Abdollahi M. (2013) Pesticides and human chronic diseases: evidences, mechanisms, and perspectives. Toxicol Appl Pharmacol. 268(2):157-77.