Mitochondrial Disorders: Inherited vs. Acquired | Mitochondrial Dysfunction: Testing Strategies. Part 3
Only in the last 60 years have we begun to understand how mitochondria work and how to differentiate inherited vs. secondary mitochondrial disorders that can trigger chronic disease. See this timeline:
I’m now going to focus on the differences between inherited and non-inherited mitochondrial disorders, and how to differentiate them based on focused functional medicine biochemical testing. Reviewing the 2 previous Substacks on mitochondrial dysfunction will help you make sense of these symptoms and testing strategies.
Inherited vs. Non-inherited Mitochondrial Disorders
Primary mitochondrial diseases are a group of genetic disorders caused by mutations in the DNA-encoding proteins involved in mitochondrial function. This usually involves mutations in the electron transport chain of the Krebs cycle and oxidative phosphorylation (OXPHOS) responsible for producing energy.
Inherited mitochondrial disorders are a genetically heterogeneous group of diseases resulting from mutations in either mitochondrial DNA (mtDNA) inherited from your mother (only maternal mitochondrial DNA is passed on to children), or from nuclear DNA (nDNA) mutations passed on from either or both parents. I took a lot genetics courses as a biology major at Northwestern University, and a genetics journal published our findings about how certain chemicals affected ovarian function in fruit flies.
(Developmental Genetics, Int. J. Insect Morphol Embryol, 7 (4), 359-375: A mutation that affects female and male germ cells differently in Drosophila Melanogaster Meign. King, Bahns, Horowitz, Larramendi. Pergamon Press, 1978.)
Not exactly what I am normally known for…!
Inherited mitochondrial disorders are like getting a new car with a built-in faulty engine, whereas non-inherited mitochondrial disorders are like having a perfect engine in your new car, but you used the wrong fuel, damaging the engine.
Common examples of mitochondrial DNA-related disorders include: Leber’s Hereditary Optic Neuropathy (LHON), which primarily affects vision; and MELAS syndrome: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes, a multisystem disorder impacting the brain, muscles, and gastrointestinal tract. In MELAS syndrome, children develop migraine-type headaches with seizures that can trigger stroke-like symptoms.
Nuclear DNA Mutations
Mutations in nuclear DNA (nDNA) involve various aspects of mitochondrial biology, not just components of the electron transport chain making energy. nDNA mutations also affect enzymes involved in metabolism, genes which involve making new mitochondria (mitochondrial biogenesis), as well as mitochondrial transport proteins to get energy inside the cell. Autosomal recessive inheritance is particularly common in nuclear DNA-related mitochondrial disorders, meaning that you must inherit 2 copies of the mutated gene (one from each parent) to be affected. Parents are typically asymptomatic carriers.
Examples of nDNA-related mitochondrial disorders include Friedrichs ataxia and Leigh’s syndrome. I saw a young girl with Leigh’s syndrome early on in my clinical career when symptoms appeared after she got Lyme disease. After getting an infection, she lost her ability to walk, and that is how her pediatrician and I got involved. This is a severe neurological disorder that typically appears in infancy or early childhood, though some cases may present later in life. It’s characterized by progressive loss of mental and motor abilities, often leading to death within a few years, usually due to respiratory failure. Symptoms vary, but common early signs include feeding difficulties, vomiting, irritability, loss of head control, and seizures. As the condition progresses, muscle weakness, lack of muscle tone, and breathing problems may develop. You learned that organs requiring high-energy output are the ones most affected by mitochondrial dysfunction, which is evident in the above syndromes affecting the eyes, hearing, brain, heart, peripheral and respiratory muscles, and gastrointestinal tract. Anytime you see a multisystemic disorder \ primarily affecting organ systems requiring high-functioning mitochondrial output, suspect a potential underlying mitochondrial disorder. This Table shows that symptoms/organs most affected:
Anyone with these symptoms needs to be evaluated for an inherited mitochondrial disorder:
Abnormal neurological functioning (seizures, developmental delays, intellectual disability, stroke-like episodes, coordination problems, muscle weakness, drooping eyelids, impaired eye movements)
Muscle fatigue/weakness/cramping/exercise intolerance
Cardiovascular problems involving cardiomyopathy (heart muscle disease), with arrhythmias
Gastrointestinal issues involving vomiting, diarrhea, abdominal pain, difficulty swallowing or poor growth
Endocrine issues (diabetes)
Sensory issues with vision and/or hearing loss
Renal disease with kidney problems
Metabolic problems like lactic acidosis (buildup of lactic acid in the body).
Non-Inherited Mitochondrial Disorders
Non-inherited mitochondrial disorders, on the other hand, refer to acquired rather than genetically predetermined mitochondrial dysfunction. This can happen from high levels of oxidative stress/reactive oxygen species which damage fragile mitochondrial components, and result from:
Infections (Lyme disease, Bartonella, viruses)
Environmental toxins (mold, pesticides, heavy metals)
A large host of metabolic or inflammatory disorders. With CFS/ME, fibromyalgia, Long Covid, neurological diseases like Alzheimer’s and Parkinson’s disease, certain autoimmune conditions, cancer, diabetes, NAFLD, cardiovascular, neuropsychiatric illness and POTS, the inflammation and oxidative stress with metabolic dysfunction impairs mitochondrial function, leading to a chronic fatiguing, musculoskeletal, neuropsychiatric condition.
The reason why secondary, non-inherited mitochondrial disorders are so frequent is that we are living in a world where it is literally impossible to avoid infections and toxins, and even common medications used to treat different diseases will adversely affect mitochondria.
Medications Adversely Affecting Mitochondrial Function
Analgesics (aspirin, acetaminophen, and other anti-inflammatory drugs such as NSAIDS)
Angina medications and anti-arrhythmics (amiodarone/Cordarone)
Anti-anxiety medications, such as alprazolam/Xanax
Antibiotics (tetracyclines)
Antidepressants, such as amitriptyline/Elavil; SSRIs, such as fluoxetine/Prozac
Anti-psychotics (haloperidol, risperidone)
Bile acid sequesters (cholestyramine/Questran, colesevelam/WelChol)
Cancer drugs
Cholesterol medications, including statins (atorvastatin/Lipitor, lovastatin/Mevacor, pravastatin/Pravachol, rosuvastatin/Crestor)
Diabetes medications (glucophage/Metformin, troglitazone, rosiglitazone)
Epilepsy medications (valproic acid/Depakote)
Mood stabilizers (lithium)
Parkinson’s disease medications (tolcapone/Tasmar, entacapone/Comtan)
Treatments for alcoholism (disulfiram/Antabuse)
Key Biochemical Tests and Genetic Markers to Evaluate Mitochondrial Function
Testing to evaluate mitochondrial function should look for the buildup of metabolic byproducts or deficiencies in energy-related compounds. The tests listed below are often the first steps to evaluate if a mitochondrial disorder is present and to rule out other conditions. They measure metabolites that could indicate impaired mitochondrial function.
1. Lactate and Pyruvate: Blood and urine analysis checking for elevated levels, particularly with an increased lactate/pyruvate ratio, can suggest a problem with the electron transport chain making energy. Pyruvate is produced at the end of glycolysis, where you break down glucose to make energy (glucose is converted into two molecules of pyruvate). Then during aerobic respiration, using oxygen, pyruvate enters the mitochondria and is converted into acetyl-CoA, which enters the Krebs cycle to generate energy through oxidative phosphorylation. Lactate levels on the other hand, come from anaerobic metabolism (a low oxygen environment, using glycolysis). When mitochondria are not functioning properly, they rely more heavily on glycolysis for ATP production (making 2 ATP) than oxidative phosphorylation (making 32 ATP), so we would expect elevated levers of lactate. However, these levels can fluctuate and may be normal in some mitochondrial disorders. It is also possible to check these levels in the cerebrospinal fluid via a spinal tap, but blood and urine testing is easier and less invasive. An exercise challenge can also be done to measure lactate at rest and after exercise.
2. Amino Acids: Elevated alanine levels in the blood or generalized aminoaciduria in the urine (from mitochondrial dysfunction affecting renal tubular function where we lose protein and amino acids in the urine) can indicate mitochondrial dysfunction. Elevated levels of glycine, proline and threonine are occasionally seen.
3. Urine Organic Acids: A comprehensive organic acid profile can check when the Krebs cycle and fatty acid oxidation are disrupted. Many functional laboratories will do urine organic acid profiles. This may reveal lactic aciduria (increased lactic acid in the urine), excess ketones, or unusual compounds reflecting impaired mitochondrial metabolism. I frequently check a biochemical marker called methylmalonic acid (MMA), an indirect marker of occult (hidden) B12 deficiency but which also indicates mitochondrial dysfunction with an inability to properly utilize B12.
4. Plasma Acylcarnitines: L-carnitine is needed to shuttle fatty acids into the mitochondria for energy production. This test measures different forms of carnitine linked to abnormal fatty acid metabolism.
5. Measuring Creatine Kinase: This is often elevated in muscle diseases including mitochondrial myopathies, indicating muscle damage.
6. Measuring Co-Q 10 Levels and Glutathione/Oxidative Stress Markers: Co-Q 10 is a vital component of the electron transport chain making energy in the Krebs cycle. Its deficiency can be primary or secondary. This is an easy test to do through local laboratories, and I occasionally find low levels in the blood. Although testing glutathione (GSH) levels or oxidative stress markers like lipid peroxides (a measure of oxidation of our fatty membranes), 8-OH d-guanine (a marker of DNA oxidative stress,) and protein carbonyls (a measure of oxidation of proteins) is not typically used to determine mitochondrial dysfunction, low levels of GSH and high levels of oxidative stress markers indirectly imply that mitochondria may be affected. These are frequently found in my patients with multiple infections and toxins.
7. Measuring Fibroblast Growth Factor 21 (FGF- 20) and Growth Differentiating Factor 15 (GDF-15): These are emerging biomarkers for more severe forms of mitochondrial dysfunction,
8. Muscle Biopsy: In cases where the diagnosis is unclear, a muscle biopsy can measure the enzymes in the respiratory chain complexes, and ‘ragged red’ fibers (abnormal clumps of mitochondria) and accumulation of lipid droplets in muscles (suggestive of impaired fatty acid oxidation) are typically found. Electron microscopy can also provide a detailed look at mitochondrial abnormalities, while extraction of mtDNA from muscle tissue can be used for genetic testing.
9. Genetic Testing: Targeted gene testing, mtDNA sequencing, and nuclear DNA gene panels as well as whole exome sequencing or whole genome sequencing, which are more comprehensive tests to identify mutations in both nDNA and mtDNA, have increasingly becoming the standard to identify complex genetic disorders.
10. Imaging Studies: A brain MRI can find basal ganglia lesions in Leigh’s syndrome, and MR spectroscopy can measure lactate levels in the brain or muscle.
Using Genetic Testing from Local Laboratories: Practical Applications
There are many laboratories that offer genetic testing, including ones like Ancestry DNA which help you discover your genetic heritage. Functional medicine practitioners I know have used Nutrigenomics and the DNA Company as labs offering actionable recommendations to reduce risk factors based on your genetic blueprint. Apart from checking mtDNA and nDNA mutations in inherited mitochondrial disorders, you can also check common genetic variants affecting your overall health. Dr Krista Kostroman, ND, who is the Chief Science Officer at the DNA Company, recently did a webinar with me on genetic testing strategies, and we discussed 3 common gene variants of interest to most:
1. UCP-1: Genes like UCP-1 give you the metabolic flexibility to burn fat more efficiently. Those with a high UCP-1 expression have higher resting metabolic rates and more resistance to weight gain and insulin resistance—they can pretty much eat whatever they want and never gain weight! Ever wonder why you gain weight just looking at food? If you don’t have this genetic variant in your brown adipose tissue, where you make heat without shivering, then you need to be much more careful with calories and diet.
2. SOD2 Gene: This is an important enzyme needed to decrease ROS and free radical stress. It’s needed for cellular health and longevity, since increased oxidative stress is implicated in aging and many chronic diseases (metabolic, cardiovascular, neurodegenerative like AD and PD). If you have a genetic variant with low SOD levels, apart from ensuring you provide your body with the nutritional components (manganese, copper) for SOD, you may need to use enhanced antioxidants (diet, nutraceuticals) to account for the increased oxidative stress adversely impacting your cellular health.
3. GPX: The glutathione peroxidase gene refers to a family of enzymes that detoxify H2O2 (hydrogen peroxide) and lipid peroxides. Abnormalities in GPX genes impairs glutathione production and subsequently increases oxidative stress leading to mitochondrial dysfunction and cellular damage. If so, using nutraceuticals like NAC (N acetyl cysteine), which acts as a precursor to GSH, may help restore intracellular GSH levels and enhance antioxidant ability; as can ALA (alpha lipoic acid) which helps regenerate GSH. Exogenous GSH can also help, but you need to use bioavailable supplements. Further research is needed to clarify optimal strategies.
Next week, Part 4 of this mitochondrial series will discuss some genetic variants which determine your psychological health (yes, your dysfunctional family may be a part of the problem, but so are your genes!), as well as specific lifestyle interventions and nutritional support that can improve mitochondrial health and optimize your chances of living a long and healthy life. Stay tuned!