The Challenges of Living with Mitochondrial Dysfunction part 2

Last month, we talked about the impact that damaged or “sick” mitochondria can have on a patient’s health and wellbeing.  A person can have a plethora of symptoms when these vital energy producing components of the cell do not function optimally.

What can we do to 1) support optimal function and 2) help to reverse the damage if it has already occurred?

David J. Miller, RPh, PhD, FIACP, FACA Owner and Chief Formulation Scientist

David J. Miller, RPh, PhD, FIACP, FACA
Owner and Chief Formulation Scientist

  1. Avoid mitochondrial toxins. In the last newsletter, I included a table that detailed some of the drugs with known mitochondrial toxicity.  Of course, it is best to eliminate or minimize exposure to these agents.  Other mitochondrial toxins include[1]:
  • Cigarette smoke
  • Air pollution and particulates
  • Poly aromatize hydrocarbons (PAHs)
  • Herbicides 2, 4-dichlorophenoxyacetic acide, dinoseb
  • mitochondrial DNA geneotoxicants, mutagens
  • infections and toxins caused by the infecting microorganisms
  • and others
  1. Patients with mitochondrial dysfunction often have different dietary needs than patients with fully functioning mitochondria.  They should be thoroughly evaluated and may need restrictions in fat, protein or carbohydrates.  They may need caloric supplementation or restriction, increased meal frequency or alternate ways of ingesting food including enteral or intravenous nutrition.  Last, if swallowing dysfunction, abnormal guy motility or gastroesophagel reflux (GERD) are obstacles, these need to be corrected to allow for proper nutritional intake.
  2. The use of supplements is not universally accepted and the literature supporting the use of nutritional supplements is sparse.  Despite this fact, the following statement was made by a group of clinicians from the Metabolic Medicine Society[2]:

Despite the paucity of high-quality scientific evidence, these therapies are relatively harmless, may alleviate select clinical symptoms, and theoretically may offer a means of staving off disease progression. Like many other mitochondrial medicine physicians, we have observed significant (and at times life-altering) clinical responses to such pharmacologic interventions. However, it is not yet proven that these therapies truly alter the course of the disease, and some experts may choose not to use these medications at all. At present, the evidence of their effectiveness does not rise to the level required for universal use.  Based on our clinical experience and judgment, however, we agree that a therapeutic trial of coenzyme Q10, along with other antioxidants, should be attempted.

  1. Co-Enzyme Q10 (CoQ10 also known is ubiquinone). CoQ10 is an important antioxidant present in all cells in the body.  Numerous factors deplete the body’s stores of CoQ10 including aging and taking certain medications like statin drugs.  Patients should take CoQ10 with a meal because it is relatively insoluble in water and needs bile from the pancreas to help with its absorption.  Recently, a more absorbable form of CoQ10 has become available called ubiquinol.  In addition to being more readily absorbed, ubiquinol is already in a “reduced” form making it a better anti-oxidant.  The only downside to using ubiquinol is that it is about 50% more expensive than ubiquinone.  This higher cost should be offset but the lower dose needed because of its better absorption.
  2. L-Carnitine. L-Carnitine plays an essential role in energy production and detoxification of the mitochondria.  L-carnitine supplementation for mitochondrial disorders is a common practice aimed at restoring free carnitine levels and removing accumulating toxic acyl compounds.  Carnitine is available as a generic or brand-name prescription (Carnitor; Sigma-Tau Pharmaceuticals, Gaithersburg, MD) for oral or IV use in mitochondrial disease. It is commonly used in combination with other vitamins and cofactors. No studies have confirmed a benefit of isolated use of carnitine in patients with primary mitochondrial disorders2.  L-Carnitine may be especially useful in acute illness and may need to be given by the intravenous route.
  3. Antioxidants are an important mainstay in treating mitochondrial disease. Antioxidants that are able to pass through the cell and mitochondrial membrane seem to be promising.  A supplement called pyruvate appears to have potential.  When researchers gave sodium pyruvate to four bed-ridden infants with mitochondrial disease, three of the four studied had significant improvement within 3 months of starting treatment[3].
  4. N-Acetyl Cysteine. N-Acetyl cysteine (NAC) serves countless roles in the body.  Among the most important is that of antioxidant.  It is an antioxidant on its own, but also stimulates the production of reduced glutathione.  NAC is actually more important as a supplement than glutathione because glutathione is not absorbed into the cells in its native form.  Despite this, glutathione is one of the most important antioxidants in the cells in the body.  NAC and glutathione serve to reduce the oxidative stress present in the mitochondria.   NAC administration has been found to be critical in defense of the kidneys following application of certain contract dyes and in defense of the liver following acetaminophen overdose.  The mechanism of this protection is due to the replenishment of glutathione that these agents cause in overdose.  NAC has also been found useful in many neurological diseases and it has been extensively studied to treat spinocerebellar ataxia, Parkinson’s disease, tardive dyskinesia, myoclonus epilepsy of the Unverricht–Lundbor type as well as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease[4].
  5. L-Arginine. Arginine is an amino acid involved in growth, urea detoxification, and creatine synthesis. L-arginine is a precursor to nitric oxide, which has neurotransmitter and vasodilatory properties.  An initial small study demonstrated that intravenous (IV) administration of L-arginine (500 mg/kg/dose) quickly decreased the severity of stroke-like symptoms, enhanced the microcirculation, and reduced tissue injury from ischemia in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes[5]. In a larger study, a decrease in clinical severity and frequency of stroke-like events was demonstrated in patients treated prophylactically with oral L-arginine (150–300 mg/kg/d). Responsive individuals tended to have baseline plasma arginine levels in the lower limits of normal. Clinicians with the metabolic medicine society have successfully used L-arginine for metabolic stroke and other types of mitochondrial disease, both as an IV medication in the acute setting and as a daily oral medication to reduce the frequency of events2.
  6. Folic Acid. Folic acid is critical for DNA production and repair in cells and well as protein metabolism.  The active form of folic acid is called methylene tetrahydrofolic acid (MTHF).  Some people are unable to convert folic acid to the active form MTHF or convert at a rate that is unable to support optimal functioning of cells and organs.  The mechanism of folate deficiency in mitochondrial disease is unclear and supplementation with MTHF for mitochondrial disease lacks strong support in the literature.  If the patients has a demonstrated genetic snip in which they cannot methylate folic acid to its active form, supplementation with MTHF may be considered.
  7. Other vitamins. Thiamine, Vitamin C, Vitamin E and alpha lipoic acid have been used in patients with mitochondrial dysfunction.  These agents have been used either individually or in combination with other agents.  Although the scientific literature supporting use of these agents is sparse,  their low toxicity profile and low cost present a relatively low risk with potential benefit.

This list seems daunting.  Keystone Pharmacy is here to help.  Please contact us.  We may be able to customize a dosage form that will simplify your therapy and make the road to better health easier to travel.

Table-1.  Medications commonly used in the treatment of mitochondrial dysfunctions (taken from 1. above, used with permission)
Dosage (pediatric)
Dosage (adult)
Adverse effects
CoQ10 as ubiquinol (preferred)
2–8 mg/kgpo daily divided in two doses
50–600 mg po daily
May obtain pretherapy level and monitor CoQ10 level in leukocytes or plasma
Wakefulness, sleep disruption; may reduce warfarin concentration
Solubilized bioavailable formulation preferred. Absorption may be improved when taken with meals
CoQ-I0 as ubiquinone
10–30 mg/kg po daily divided in 2 doses
300–2400 mg po daily divided 2–3 times a day
May obtain pretherapy level and monitor CoQ10 level in leukocytes or plasma
Wakefulness, sleep disruption; may reduce warfarin concentration
Less potent than ubiquinol and less well absorbed; solubilized bioavailable formulation preferred. Absorption may be improved when taken with meals
Riboflavin (B2)
50–400 mg po daily
50–400 mg po daily
Not usually done
High doses may cause anorexia and nausea
Changes urine color and smell; effects may be minimized by giving at bedtime
0.1 g/kg po daily; maximum 10 g/d
5 g po daily, given 1–2 times per day
Renal function
GI upset
Primarily used in myopathy patients, though evidence exists for routine use in all mitochondrial disease patients; converted to creatinine in the gut
Acute stroke: 500 mg/kg IV per day for 1 –3 days; Maintenance: 150–300 mg/kgpo or IV daily divided 2–3 times a day
Acute stroke: 500 mg/kg IV per day for 1–3 days; Maintenance: 150–300 mg/kg po or IV daily divided 2–3 times a day
Plasma arginine in amino acid profile
Hypotension (with IV loading), hyponatremia, headache, nausea, diarrhea. Myelinolysis reported with high dose in single case
Used with metabolic strokes, especially in MELAS or in those with low-normal plasma arginine; citrulline is used in urea cycle defects as an alternative to arginine
10–100 mg/kg per day IV or po divided 3 times a day
100–1000 mg per dose, given IV or po 2–3 times a day
Pretherapy free and total plasma carnitine levels
GI upset, fishy odor (due to bacterial degradation; may be improved with antibiotic). Reports of cardiac rhythm disturbances in long-chain fatty acid oxidation defects
FDA-approved for metabolic diseases; available as prescription generic and brand. Only 10%–20% absorbed. Acetyl-carnitine is an alternative
B50 or B100 (B vitamin complex)
1 tab po given 1–2 times a day
1 tab po given 1–2 times a day
Not usually done
Toxic neuropathy may occur with chronic use of larger doses than recommended
Poorly palatable
Vitamin E
1–2 IU/kg po daily
100–200 IU po daily
Not usually done
Possible adverse cardiac risks at doses > 400 IU/d
Absorption may be improved when taken with meals
Vitamin C
5 mg/kg po daily
50–200 mg po daily
Not usually done
Increases iron absorption; high doses may cause renal insufficiency (single case report)
Easily absorbed water-soluble vitamin
N-Acetyl Cysteine
None known
Nausea, vomiting, diarrhea possible.
Unpleasant taste may make it hard to take if in liquid form
Alpha-lipoic acid
50–200 mg/d
50–200 mg/d
Not usually done
None known
Folic acid as leucovorin, containing both D and L isomers
0.5–1.5 mg/kg po daily, given 1–2 times per day (higher doses are used in folinic acid-responsive epilepsy)
2.5–25 mg po daily given 1–2 times per day
May assess spinal fluid folate and plasma/urine pipecolic acid
Rash and pruritus
Cerebral folate can also be replenished with Isovorin (L-isomer, active form) or 5-methyl-tetrahydrofolate (Deplin), the natural transport form of folate across the blood-brain barrier. Consider for patients with symptom worsening or with proven cerebral folate deficiency

*CoQ10 and a B vitamin are the most commonly used medications in a starting “mitochondrial treatment cocktail.

CoQ10—coenzyme Q10; FDA—US Food and Drug Administration; GI—gastrointestinal; IV—intravenous; MELAS—mitochondrial encephalomyopathy, lactic acidosis, and stroke like episodes; po—by mouth.

[2] Sumit Parikh, MD, Russell Saneto, DO, PhD, Marni J. Falk, MD, Irina Anselm, MD, Bruce H. Cohen, MD, Richard Haas, MB, BChir, MRCP, and The Mitochondrial Medicine Society.  A Modern Approach to the Treatment of Mitochondrial Disease.  Curr Treat Options Neurol. 2009 Nov; 11(6): 414–430
[3] Saito K, Kimura N, Oda N, Shimomura H, Kumada T, Miyajima T, Murayama K, Tanaka M, Fujii T.  Pyruvate therapy for mitochondrial DNA depletion syndrome.  Biochim Biophys Acta. 2012 May;1820(5):632-6. doi: 10.1016/j.bbagen.2011.08.006. Epub 2011 Aug 11.
[4] Reza Bavarsad Shahripour Mark R Harrigan and Andrei V Alexandrov.  N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities Brain Behav. 2014 Mar; 4(2): 108–122.
[5] Koga Y, Ishibashi M, Ueki I, Yatsuga S, Fukiyama R, Akita Y, Matsuishi T.  Effects of L-arginine on the acute phase of strokes in three patients with MELAS.  Neurology. 2002 Mar 12; 58(5):827-8.
This entry was posted in General and tagged , , , , , . Bookmark the permalink.

Leave a Reply

Your email address will not be published. Required fields are marked *