Mitochondria: Functional vs Dysfunctional

Mitochondrial Dysfunction

 

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For an in-depth webinar on Mitochondrial Dysfunction:

Mitochondrial Dysfunction and Nicotinamide Riboside webinar

 

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Definitions and Terms Related to Pain

 

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Mitochondria

Mitochondria are generally considered to be the “powerhouses” of cells in that they are the critical structures within all living cells that process food into energy. In addition to providing energy, they manufacture enzymes and they play a major role in maintaining appropriate balance of free radicals to combat oxidative stress. Oxidative stress is a condition that contributes to the breakdown and damage of cells, DNA, RNA and proteins that is associated with aging and disease. Mitochondria impact the metabolism of all cells and therefore play a huge role in health. When there is dysfunction within mitochondria, any number of health problems manifest including insulin resistance and diabetes, obesity, cardiovascular diseases including congestive heart failure, fibromyalgia, neurodegenerative  diseases such as Parkinsons and others.
Nicotinamide Adenine Dinucleotide (NAD)
The process of obtaining energy from food requires the transfer of electrons and this transfer requires a co-enzyme, nicotinamide adenine dinucleotide (NAD), which exists in two form, NAD+ and NADH, depending on whether it is holding the electron. Via biochemical pathways, the electron transfer from NAD+ provides for the creation of ATP, the molecule that provides energy for cells. But NAD+ is also required for modulating free radicals, so a balance must occur between these two functions.  As we age there is decreased production of NAD+ and when energy production goes down, metabolic function is impaired and as free radicals increase there is greater damage to DNA, RNA and proteins, etc, leading to further metabolic dysfunction, cellular degeneration follows, leading to the many disease processes noted above.
 
There is a great deal of interest in current research in the use of intravenous NAD+ for the management of acute opioid and alcohol withdrawal. While still in early clinical research studies, the findings have been dramatic, showing extraordinary effectiveness in eliminating the withdrawal symptoms and cravings associated with discontinuing addictive use of opioids and alcohol. Anecdotal reports of NAD+ in the treatment of Parkinson’s Disease, chronic migraine headaches and other chronic pain syndromes have also suggested dramatic benefits. Anecdotal reports of intranasal formulations of NAD+ have also shown promise in their usefulness. Additional research is ongoing.
Mitochondria Dysfunction
As energy production goes down, fatigue develops and impaired physical indurance even when more calories are ingested. This is the hallmark of obesity and fibromyalgia and electron microscopic studies reveal mitochondria to be structurally and functionally impaired. Mitochondrial dysfunction then leads to the metabolic impairment found in insulin resistance and diabetes, obesity, vascular disease, cardiovascular disease, fatty liver and increased inflammatory conditions. It also contributes to mood disorders including depression and bipolar disorders as well as premature aging.
What Can be Done for Mitochondrial Dysfunction?

Cells have the capacity to repair damaged mitochondria and improve mitochondrial function, a process called mitochondrial biogenesis. Improving mitochondrial function can result in reduced fatigue and greater physical endurance with increased lean muscle mass, improved glucose metabolism, insulin resistance and cardiac function. It will also contribute to weight loss and improved mood.

Mitochondrial biogenesis requires turning on specific genes in the cell that stimulate cellular DNA and RNA to promote protein synthesis. This process is regulated by PGC1-alpha (PPAR-gamma Co-Activator 1-alpha) which in turn is activated by a chemical, Sirtuin 1 (SIRT1). The sirtuins are chemicals that regulate genes, turning them on or off and they require NAD+ as a source of energy. It is believed that the chronic state of NAD+ depletion associated with conditons of oxidative stress results in a deficiency in SIRT1 activity and the end result of mitochondrial dysfunction due to inadequate mitochondrial maintenance and repair. When SIRT1 is up-regulated, or stimulated, mitochondrial biogenesis can proceed with the associated benefits.

 

Up-Regulating SIRT1

Recent research reveals that up-regulating SIRT1 can be achieved by vigorous exercise, caloric restriction and fasting, and by NRF2 activation. However,  activating SIRT1 via NRF2 activation alone without adequate NAD+ production is ineffective. Human studies confirm the benefits of caloric restriction and fasting but specific guidelines identifying the degree of caloric restriction  and the length of fasting required are lacking (see references below).

See: NRF2 Activators

 

Nicotinamide Riboside (NR)

Nicotinamide Riboside (NR) is a variant of niacin, Viamin B-3, that is a precursor (building block) for the manufacture of NAD+ and is known to up-regulate sirtuin 1. While supplementing with niacin also can contribute to increasing NAD+ levels, it is associated with side effects and it down-regulates SIRT1  and is not believed to benefit mitochondrial biogenesis. A significant number of animal and lab studies as well as a growing number of human studies suggest that NR can be very effective in improving mitochondrial function and improve the consequences of mitochondrial dysfunction described above.

See: Nicotinamide Riboside – NR

 

Coenzyme Q10 (CoQ10)

Coenzyme Q10 (CoQ10) is an antioxidant noted to have high levels in healthy mitochonria that is critical in mitochondrial function.  CoQ10 levels (as measured in blood mononuclear cells) have been noted to be low in fibromyalgia (FM) patients and  treatment with CoQ10 has been found to improve multiple symptoms of FM.

See: CoQ10

 

Alpha Lipoic Acid  (ALA) and Acetyl L-Carnitine

Alpha lipoic acid (ALA), a mitochondrial nutrient, offers protective effects and possible improvements in age-associated cognitive and mitochondrial dysfunction of the brain. ALA improves age-associated decline of memory, improves mitochondrial structure and function, inhibits age-associated increase of oxidative damage, elevates the levels of antioxidants, and restores the activity of key enzymes. In addition, co-administration of ALA with other mitochondrial nutrients, such as acetyl-L-carnitine and coenzyme Q10, appears more effective in improving cognitive dysfunction and reducing oxidative mitochondrial dysfunction.

 

Mitochondria Dysfunction and Fibromyalgia
There is growing evidence that fibromyalgia (FM), a condition associated with chronic widespread pain, fatigue and non-restful sleep along with cognitive impairment, may have an underlying pathophysiology of mitochondrial dysfunction. This could explain many of the symptoms of FM as well as the benefit sometimes seen with exercise and fibromyalgia.
 
 

Anti-Aging

 

References:

 Mitochondrial – Overview 

See: Antioxidants and Oxidative Stress

 

  1. Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS) – 2014
  2. The Mitochondrial Basis of Aging and Age-Related Disorders – 2017

Mitochondrial Dysfunction – Treatment: Overview

  1. Mitochondrion-Permeable Antioxidants to Treat ROS-Burst-Mediated Acute Diseases – 2016 no highlights
  2. Current Experience in Testing Mitochondrial Nutrients in Disorders Featuring Oxidative Stress and Mitochondrial Dysfunction
  3. Mitochondrial biogenesis: pharmacological approaches. – PubMed – NCBI
  4. The mitochondrial cocktail: rationale for combined nutraceutical therapy in mitochondrial cytopathies. – PubMed – NCBI
  5. Oxidative Stress and Mitochondrial Dysfunction across Broad-Ranging Pathologies – Toward Mitochondria-Targeted Clinical Strategies
  6. Daily Nutritional Dose Supplementation with Antioxidant Nutrients and Phytochemicals Improves DNA and LDL Stability
  7. Melatonin-Mitochondria
  8. Remedying the Mitochondria to Cure Human Diseases by Natural Products – 2020

 

Mitochondrial Dysfunction –  Treatment: Alpha-Lipoic Acid & L-Carnitine

  1. The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction 2008 – PubMed – NCBI
  2. Effect of Combined Treatment with Alpha Lipoic Acid and Acetyl-L-Carnitine on Vascular Function and Blood Pressure in Coronary Artery Disease Patients
  3. Effects of L-carnitine supplementation on oxidative stress and antioxidant enzymes activities in patients with coronary artery disease

 

Mitochondrial Dysfunction –  Treatment: Coenzyme Q10 (CoQ10)

  1. Bioenergetic and antioxidant properties of coenzyme Q10: recent developments. – PubMed – NCBI
  2. Coenzyme Q10 as a therapy for mitochondrial disease. – PubMed – NCBI
  3. Effect of Coenzyme Q10 supplementation on mitochondrial electron transport chain activity and mitochondrial oxidative stress in Coenzyme Q10 defici… – PubMed – NCBI
  4. Elucidation of molecular mechanism involved in neuroprotective effect of Coenzyme Q10 in alcohol-induced neuropathic pain – Kandhare – 2012 – Fundamental & Clinical Pharmacology – Wiley Online Library
  5. Protective effects of coenzyme Q10 and L-carnitine against statin-induced pancreatic mitochondrial toxicity in rats – 2017

 

Mitochondrial Dysfunction –  Depression

  1. Role of Sirtuins in Linking Metabolic Syndrome with Depression – 2016

 

Mitochondrial Dysfunction –  Fibromyalgia

  1. Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients – implications in the pathogenesis of the disease
  2. Could mitochondrial dysfunction be a differentiating marker between chronic fatigue syndrome and fibromyalgia? – PubMed – NCBI
  3. Is Inflammation a Mitochondrial Dysfunction-Dependent Event in Fibromyalgia? – 2012
  4. The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia – 2013 – PubMed – NCBI
  5. The Neuro-Immune Pathophysiology of Central and Peripheral Fatigue in Systemic Immune-Inflammatory and Neuro-Immune Diseases – 2015
  6. Oxidative stress and mitochondrial dysfunction in fibromyalgia. – PubMed – NCBI

 

Mitochondrial Dysfunction –  Pain

  1. Mitochondrial and bioenergetic dysfunction in trauma-induced painful peripheral neuropathy – 2015
  2. Roles of Reactive Oxygen and Nitrogen Species in Pain – 2011 

 

Mitochondrial Dysfunction –  Peripheral Neuropathy

  1. Mitochondrial and bioenergetic dysfunction in trauma-induced painful peripheral neuropathy – 2015

 

NAD/NR –  Overview

  1. Caloric Restriction, Fasting and Nicotinamide Riboside | Anti-Aging | Articles | Magazine
  2. First-human-clinical-study-of-ChromaDexs-NIAGEN-nicotinamide-riboside-meets-primary-endpoint
  3. Nicotinamide riboside, a trace nutrient in foods, is a vitamin B3 with effects on energy metabolism and neuroprotection. – PubMed – NCBI
  4. The Secret Life of NAD+: An Old Metabolite Controlling New Metabolic Signaling Pathways – 2010
  5. NAD+ metabolism in health and disease. – PubMed – NCBI
  6. NAD+ and Sirtuins in Aging and Disease – 2014
  7. NAD+ Metabolism and the Control of Energy Homeostasis – A Balancing Act between Mitochondria and the Nucleus
  8. NAD+ and NADH in brain functions, brain diseases and brain aging. – PubMed – NCBI

 

NAD/NR – Aging

  1. Vitamins and Aging – Pathways to NAD+ Synthesis – 2007
  2. A New, Reversible, Cause of Aging | HMS

 

NAD/NR – Brain Inflammation

  1. Treatment of Brain Inflammatory Diseases by Delivering Exosome Encapsulated Anti-inflammatory Drugs From the Nasal Region to the Brain – 2011

 

NAD/NR – Caloric Restriction

  1. Caloric Restriction, Fasting and Nicotinamide Riboside | Anti-Aging | Articles | Magazine
  2. Metformin and caloric restriction induce an AMPK-dependent restoration of mitochondrial dysfunction in fibroblasts from Fibromyalgia patients. 2015 – PubMed – NCBI
  3. Caloric restriction: from soup to nuts. – PubMed – NCBI
  4. Calorie restriction – Wikipedia
  5. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. – 2007

 

NAD/NR – Fibromyalgia

  1. The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients – 2013

 

NAD/NR – Intranasal

  1. NAD+ and NADH in cellular functions and cell death. – PubMed – NCBI

 

NAD/NR – Mitochondrial disorders

  1. The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients – 2013
  2. NAD+ Metabolism and the Control of Energy Homeostasis – A Balancing Act between Mitochondria and the Nucleus
  3. Pharmacological NAD-Boosting Strategies Improve Mitochondrial Homeostasis in Human Complex I-Mutant Fibroblasts. – PubMed – NCBI
  4. The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction – 2008

 

NAD/NR – Obesity


  1. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet induced obesity – 2012
  2. Milk Ingredient Nicotinamide Riboside ‘Helps Prevent Obesity’ And Burns Fat
  3. Niagen nicotinamide riboside may reduce obesity-related inflammation

 

NAD/NR – Oxidative Stress and Reactive Oxygen Species (ROS)

  1. Crosstalk between Oxidative Stress and SIRT1 – Impact on the Aging Process – 2013
  2. Reactive oxygen species and mitochondria – A nexus of cellular homeostasis – 2015

 

NAD/NR – Sirtuins

  1. Nicotinamide Riboside Promotes Sir2 Silencing and Extends Lifespan via Nrk + and Urh1:Pnp1:Meu1 Pathways to NAD -2007
  2. SIRTUIN 1 AND SIRTUIN 3 – PHYSIOLOGICAL MODULATORS OF METABOLISM – 2012
  3. Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging – 2013
  4. Targeting SIRT1 to improve metabolism – all you need is NAD+? – 2012
  5. Role of Sirtuins in Linking Metabolic Syndrome with Depression – 2016

 

Emphasis on Education

 

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