dysautonomia mitochondrial dysfunction

Digging Deeper into Mitochondrial Dysfunction

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When you have a hammer, everything becomes a nail, or so they say. I worry about this as I dig deeper into mitochondrial dysfunction. Could all of these disparate symptoms and conditions have their roots in the mitochondria? Could it be that simple? Perhaps. More and more, as I search for explanations for the devastating symptoms that so many of our readers report, the research I find points to mitochondrial dysfunction. Sure, changes in gut microbiota and function are apparent and often related and certainly immune dysregulation is a component of these illnesses, but the underlying connection among these disturbances seems inevitably and inextricably linked to dysfunctional mitochondria as the central hub of illness. Heal the mitochondria, heal the body is quickly becoming my new mantra.

Mitochondria as Danger Sensors

Some researchers argue that the mitochondria are the danger sensors for host organisms; having evolved over two billion years to identify and communicate signs of danger to the cells within which they reside. The signaling is simple and yet highly refined, involving a series of switches that control cellular energy, and thus, cellular life or death. When danger is present, energy resources are conserved and the immune system fighters are unleashed. When danger is resolved, normal functioning can resume.

If the danger is not resolved and the immune battles must rage on, the mitochondria begin the complicated process of reallocating resources until the battle is won or the decision is made to institute what can only be described as suicide – cell death. Cell death is a normal occurrence in the cell cycle of life. Cells are born and die for all manner of reasons. But when cell death occurs from mitochondrial injury, it is messy, and evokes even broader immune responses, setting a cascade in motion that is difficult to arrest.

And, if the on the battlefield, the host army is understaffed and under-resourced, no matter how hard the immune fighters battle, the fight will be lost, maybe not immediately, but eventually. All sorts of mechanisms will be employed to reallocate and reinforce needed battlements, but they will be for naught, further depleting already scarce host resources, until the decision is made, within the mitochondria, to begin pulling back, withdrawing, and ultimately casting the final orders of cell death.

It’s not Autoimmunity, but Impaired Immunity

I never much liked the war model of health and disease, but it seems to work well as metaphor for immune functioning, as it is far more illustrative and useful than the self-versus non-self-characterization. Really, what army with two billion years of experience, one that contains all of the memories and skills of battles past, would misidentify itself and begin broad scale fratricide  – kill itself and its brethren for no other reason but mistaken identity and do so for years on end?  Sure, there can be errors, over compensation and other weaknesses in the immune system, but not continued aggression towards itself in some maladaptive response. That makes no sense and contradicts the very notion and function of an immune system – to keep the host organism alive and well. Indeed, when we consider the trillions of microbes – clear non-self entities – that live inside and upon us, the idea that the immune system evolved simply to kill the non selves seems laughable. And so, I reject the concept of autoimmunity, not because the patients who suffer from continued immune system activation are not ill, they are, but because the concept of autoimmunity belies the very nature of immune function and severely limits possible approaches to recovery.

The Naming of Things

Many of you might be thinking ‘what the heck does what we name things have to do with understanding illness?’  Well, the language and the characterization of disease impacts therapeutic choices. In a system where autoimmunity dominates the discussion, survival is predicated on suppressing the invading immune army. Consequently, most therapeutic options for autoimmune disease are immunosuppressant, and mostly they fail. In contrast, if one characterizes immune function by its ability to protect and sustain life by fending off dangers or threats to survival, be they self or non-self, it does not matter, then we can be open to finding causes for those failed battles. We can ask questions like: what resources are missing that would allow the immune army to fend off the danger once and for all or what could heal the damaged cells, scavenge toxicants and oxidants or re-calibrate mitochondrial energy production? When we re-frame the discussion in this way, we open the door to a deeper understanding of health and disease. It is from this perspective, one that says chronic immune activation is not a disease itself but a symptom of an on-going and failing immune battle, that we can get to the mitochondria as the central hub for chronic ill-health.

Evolution and the Mighty Mitochondria

Mitochondria are interesting little buggers, having evolved from the very parasites our immune system sought to protect us against. Called symbionts, the mitochondria were microbial intruders swallowed by the host. In a brilliant move of survival, they somehow convinced the host organism not only not to kill them but to let the mitochondria, a parasitic intruder, run the host’s energy supply. The mitochondria proved their utility and developed a symbiotic relationship with the cells within which they resided. Over time, mitochondria developed a myriad of intricate communication and resource allocation mechanisms to ensure not only their survival but that of their host organism. And so, in many ways, the mitochondria evolved as part of a cooperative and collaborative ecosystem; one in which they sense and communicate danger to the rest of the organism, and if need be, initiate the final death programs; something, they should be loath to do, since their survival depends entirely on host survival.

Clearly though, and from the very beginning, the mitochondria positioned themselves as the brains of the operation. Mitochondria control energy. There is no other resource more important to the living organism than energy. Consider the most consistent sickness behaviors across all illness include, lethargy, fatigue, sleepiness, often followed by muscle and body aches, anorexia or the loss of interest in eating. The reduction in energy is purely a function of mitochondrial resources. The achy muscles are moderated by mitochondrial retractions of energy and the loss of appetite too, mitochondrial diminishments – recall the orexin/hypocretin system. By whatever pathway, declining mitochondrial energy production arises when danger signals, or more appropriately, cell damage signals are communicated. It is then that the immune armies are activated and inflammation sequences unleashed.

What Does Mitochondrial Dysfunction Look Like?

Everything and nothing at the same time. Mitochondrial dysfunction doesn’t lead to one, clear cut disease, even when there are clear genetic markers, but predisposes one to everything. Where mitochondrial damage is felt and the subsequent immune events present is complex and dependent upon the interactions among the host organism’s innate predispositions, environmental exposures and nutritional status, with the latter two significantly influencing each other. The microbial composition of the host, especially in the gut, but also on the skin and the various mucous membranes that interface with the outside world, can also moderate or trigger the danger signals that lead to mitochondrial dysfunction. More often than not though, mitochondrial damage is felt where oxygen demands are greatest, the brain, the heart, the gut, the muscles. Diseases that are currently identified discretely might all have common symptoms – the mitochondria.

Certainly, chronic fatigue should be considered mitochondrial in nature. I don’t think there is a more clear-cut example of mitochondrial dysfunction than severe fatigue, muscle pain and weakness. The question becomes, from where does the dysfunction originate and how can it be fixed or healed?

Migraine, seizures, ataxias and other neurological disorders are emerging as mitochondrial, particularly was more work is done on the hypocretin/orexin system.

Autonomic dysregulation, recognized under the umbrella as dysautonomias are mitochondrial in nature.

Thyroid dysfunction is likely mitochondrial in nature; the interaction between thyroid hormones and mitochondria is direct. Given the mitochondria’s role in steroidogenesis, other hormone systems are likely modulated by mitochondrial functioning.

Research is emerging suggesting that gastrointestinal disturbances, particularly those of dysmotility like IBS, gastroparesis, constipation and pseudo obstruction but also anorexia are mitochondrial in nature. Indeed, the GI system has its own nervous system, called the enteric nervous system. Only 10-15% of GI motility is controlled from brain’s autonomic system. The rest is controlled on site by the enteric system, mostly from cells called the interstitial of cells Cajal – the smooth muscle cells that propagate contractility and rhythm and form the gut barrier between the inside contents and the rest of the body.  The mitochondria control energy usage and production here. Mess with these cells, diminish oxygen usage, pull back energy production and all sorts of things go wrong. We can get ill-timed contractions or no contractions at all, making the movement of food stuffs through the GI impossible. Poor absorption and metabolism of nutrients, and increased permeability of the tight junctions allowing for the leaky gut scenario common in many chronic conditions, become prominent and are also symptoms of mitochondrial dysfunction. Even anorexia, the will to eat, can be disturbed significantly by mitochondrial damage.

And I suspect, although I have no evidence to support this claim, in women, mitochondrial damage can express itself in the reproductive organs, especially when oxygen demands are greatest, menstruation and pregnancy. Consider the increasingly painful muscle contractions for some women involved in shedding the uterine lining during menstruation, just as diminished oxygen and energy in other muscles begins the cycle of lactate production and buildup that initiates pain, so too might this happen in the uterus. As mitochondrial deficiencies persist, uterine dysfunction would grow and compensatory immune system mechanisms increase until the compensatory mechanisms take a life of their own. When we consider the mitochondrial influence on GI motility, their influence on uterine function is not difficult to imagine. I have an inkling that endometriosis, the excessive growth of endometrial cells first within the uterus and then in regions of the body where they ought not be, is a protective mechanism, albeit an aberrant and problem causing one, that indicates increased mitogenesis and cell growth as a compensatory reaction to some original mitochondrial inadequacy. How this might happen molecularly provides some intriguing possibilities.

Immune function and inflammatory reactions are directly controlled by mitochondrial signals of danger and so to the extent we see chronic inflammatory conditions, one can look towards mitochondrial resources and the ensuing danger signals for clues towards reducing these reactions. While much of the clinical research is nascent, more and more clinicians, often from disparate specialties and sometimes without recognizing the immune-mitochondrial connections, have made great inroads towards healing and restoring mitochondrial function through diet and nutritional supplementation paired with the reduction and removal of environmental and medical toxins and dietary inflammasomes.

Is Everything a Nail, When One has a Hammer?

Maybe, but I can’t help but thinking that this mitochondrial hammer might be the one to hit the nail on the head and finally make some inroads towards reducing the suffering and burden of chronic disease. Only time will tell. For the moment, however, this is a hammer that deserves more recognition and whether it turns out to be the final clue or not one thing is clear, mitochondrial health is critical for human health. Deny the mitochondria their due and chronic, complicated illness will persist.

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Image credit: OpenStax, CC BY 4.0, via Wikimedia Commons

This article was published previously on Hormones Matter in June 2014.

Cyclic Vomiting Syndrome and Mitochondrial Dysfunction: Research and Treatments

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Cyclic vomiting syndrome (CVS) is a debilitating disease characterized by episodes of severe nausea and persistent vomiting interspersed with periods of wellness. CVS affects about 2 percent of school-aged children, and also affects adults, although in adults it is often not recognized. Getting a diagnosis can be challenging, and sometimes takes a long time. Episodes of CVS can be extremely debilitating, and are sometimes difficult to treat and require hospitalization.

My daughter has suffered from this disease for 10 years, since she was 2 years old (see her story here). Her episodes were somewhat predictable when she was younger, but have changed and become less predictable, and more difficult to manage with medication, as she gets older. Although we try to avoid triggers such as stress and fatigue, being a pre-teen girl, she likes to have sleepovers with her friends and stay up chatting all night.  Unlike other pre-teen girls, however, she suffers the aftereffects of the sleepovers sometimes by vomiting for 24 hours or more.

What Causes Cyclic Vomiting Syndrome?

Although it has long been thought to be related to migraines, many sources state that the cause of cyclic vomiting syndrome is not known. Mechanisms that may be involved include episodic dysautonomia (malfunction of the autonomic nervous system that can result in a variety of symptoms), mitochondrial DNA mutations that cause deficits in cellular energy production, and heightened stress response that causes vomiting. However, there is mounting evidence for the role of mitochondrial dysfunction in the pathogenesis of this disease, a fact that is not often understood by the average practicing gastroenterologist. The connection to mitochondrial dysfunction has important implications for effective treatment of cyclic vomiting syndrome.

Mitochondrial Dysfunction, Cyclic Vomiting and Other Conditions

Mitochondria are small organelles within the cell responsible for energy production and other critical functions. Because of these crucial functions, Dr. Richard Boles, Director of the Metabolic and Mitochondrial Disorders Clinic at Children’s Hospital Los Angeles, explains that “30 years or so ago, many scientists couldn’t believe that mitochondrial disease could exist, because how does the organism survive?” However, mitochondrial dysfunction plays a role in many diseases, including CVS, and according to Dr. Boles:

“these are partial defects. Mitochondrial dysfunction doesn’t really cause anything, what it does is predisposes towards seemingly everything. It’s one of many risk factors in multifactorial disease. It can predispose towards epilepsy, chronic fatigue, and even autism, but it doesn’t do it alone. It does it in combination with other factors, which is why in a family with a single mutation going through the family, everyone in the family is affected in a different way. Because it predisposes for disease throughout the entire system.”

DNA mutations that affect mitochondrial function can occur in the DNA that is found in the nucleus of the cell (genomic DNA), or they can occur in the DNA that is found within the mitochondria themselves. Mitochondrial DNA is inherited differently than nuclear DNA. Most people are familiar with the inheritance of nuclear DNA, in which we have two copies of every gene, and we inherit one copy from each of our parents. However, mitochondrial DNA is inherited exclusively through the mother; therefore, mutations that affect the mitochondrial DNA can be traced through the maternal lineage of a family.

A possible relationship between cyclic vomiting syndrome and mitochondrial dysfunction was suggested by the finding that in some families, CVS was maternally inherited. Mitochondrial DNA mutations and deletions have been reported in patients with CVS, and disease manifestations of mitochondrial dysfunction have been found in the maternal relatives of patients with CVS. In other words, conditions such as migraines, irritable bowel syndrome, depression, and hypothyroidism, are often found in the maternal relatives of patients with CVS.

Mitochondrial DNA mutations don’t cause CVS directly, in the way that a DNA mutation causes cystic fibrosis, for example. In some patients, mitochondrial dysfunction plays a greater role in the causation of their disease, and in other patients, it may be less of a factor. Dr. Boles explains: “In some cases it’s a clear mitochondrial disorder, they have multiple other manifestations and it drives the disease. However, in most patients, it is one of many factors in disease pathogenesis.” Patients with classical mitochondrial disorders have disease manifestations such as muscle weakness, neurological problems, autism, developmental delays, gastrointestinal disorders, and autonomic dysfunction. Some patients with CVS have these other disease manifestations, and some have only CVS symptoms.

Treatment for Cyclic Vomiting Syndrome and Mitochondrial Dysfunction

As with many diseases, understanding as least some of the cause of CVS has allowed for the development of treatments tailored towards fixing the root cause. Co-enzyme Q10 and L-carnitine are two dietary supplements that have been used to treat a wide variety of conditions.  Both supplements may be able to assist the mitochondria with energy production and thus, help compensate for mitochondrial dysfunction. A retrospective chart review study found that using these two supplements, along with a dietary protocol of fasting avoidance (having three meals and three snacks per day), was able to decrease the occurrence of, or completely resolve, the CVS episodes in some patients. In those patients who didn’t respond to treatment with supplements alone, the addition of amitriptyline or cyproheptadine, two medications that have been used for prevention of CVS episodes, helped to resolve or decrease the episodes. Treatment with the cofactors alone was well tolerated with no side effects, and treatment with cofactors plus amitriptyline or cyproheptadine was tolerated by most patients. Therefore effective treatment for prevention of CVS episodes does exist, although it may not be widely employed by most gastroenterologists.

My daughter is currently trying to treat her CVS with the combination of co-enzyme Q10 and L-carnitine. So far she hasn’t experienced any side-effects, and over the next few months we will see if she experiences a decrease or even a complete cessation of her episodes. My hope for her is that she won’t have to choose between missing out on a fun night with her friends, and being able to be functional for the rest of the weekend. Maybe she can be like every other teenager and go to a sleepover, and just be grumpy the next day, instead of spending the next day vomiting and lying on the bathroom floor in pain.

Dr. Richard Boles, MD:  Dr. Boles completed medical school at UCLA, a pediatric residency at Harbor-UCLA, and a genetics fellowship at Yale. He is board certified in Pediatrics, Clinical Genetics and Clinical Biochemical Genetics. His current positions include Associate Professor of Pediatrics at the Keck School of Medicine at USC, an attending physician in Medical Genetics at Children’s Hospital Los Angeles, and Medical Director of Courtagen Life Sciences. Dr. Boles practices the “bedside to bench to bedside” model of a physician-scientist, combining an active clinical practice in metabolic and mitochondrial disorders with clinical diagnostics (DNA testing) and research. Dr. Boles’ clinical and research focus is on polymorphisms (common genetic changes) in the DNA of genes involved in energy metabolism, and their effects on the development of common functional disorders. Examples include migraine, depression, cyclic vomiting syndrome, complex regional pain syndrome, autism and SIDS. He has 50 published papers on mitochondrial disease.

Postscript: Using this advice, we were able to manage my daughter’s vomiting. Here is the follow-up story.

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter.

This article was first published on January 28, 2014.