Mitochondrial Direct Nutraceuticals, LLC 
Mitochondrial Dysfunction Research
Mitochondrial dysfunction is a major causative factor in disease
10 Chronic Diseases linked to mitochondrial dysfunction
Experimental and Molecular Pathology

Mitochondrial dysfunction and
molecular pathways of disease

Steve R. Pieczenik, John Neustadt
Received 30 August 2006
Available online 18 January 2007
"Since the first mitochondrial dysfunction was described in the 1960s, the medicine has advanced in its understanding the role mitochondria play in health, disease, and aging. “
“If in the next 50 years advances in mitochondrial treatments match the immense increase in knowledge about mitochondrial function that has occurred in the last 50 years, mitochondrial diseases and dysfunction will largely be a medical triumph.”
“A wide range of seemingly unrelated disorders, such as;

schizophrenia, bipolar disease, dementia, Alzheimer's disease, epilepsy, migraine headaches, strokes, neuropathic pain, Parkinson's disease, ataxia, transient ischemic attack, cardiomyopathy, coronary artery disease, chronic fatigue syndrome, fibromyalgia, retinitis pigmentosa, diabetes, hepatitis C, and  primary biliary cirrhosis

have underlying pathophysiological mechanisms in common, namely ROS production, the accumulation of mtDNA damage, resulting in mitochondrial dysfunction.”
"Mitochondrial dysfunction has been implicated in nearly all pathologic and toxicologic conditions."
"Antioxidant therapies hold promise for improving mitochondrial performance."
What are Mitochondria and what functions do they perform? 
As noted in the photo below, mitochondria are tubular or oblong shaped and are bounded by double membranes. Mitochondria play a central role in cell life, cell death and human health. An increasing number of clinical studies place mitochondrial dysfunction at the heart of virtually every disease we know of. Research also shows that many prescribed drugs cause mitochondrial damage.
Mitochondria are organelles that perform a very critical role as the cell's electrical(energy) producers. In many ways, mitochondria act like the cells digestive system in that they take in nutrients and break them down in order to create usable energy called ATP.
This process of generating energy within the cell is known as cellular respiration. If cellular respiration is low resulting in cellular malfunctions, it may be an indication of some form of mitochondrial dysfunction within the cell rather than some predisposed genetic defect. Most of the chemical reactions involved in cellular respiration happen within the mitochondria as they convert energy into forms that are usable by the cell.
The number of mitochondria in a cell can range from a few to several thousand, depending on the energy requirements of each cell. Cells known to have the highest energy requirements and therefore, the highest number of mitochondria are muscle, heart, liver, kidney, and brain cells.
Genetics vs Metabolics

Poly-MVA formulation scavenge free radicals(ROS)
while transporting Electrons(Energy), Vitamins, Minerals
ATP Co-Factors directly to mitochondria.
Over 50 years ago, most scientific and medical therapeutic
approaches focused on cellular metabolism.

With the advent of genetics, a concentrated shift toward genomics, and subsequently proteomics (protein profiles), dominated the therapeutic stage.
The area of metabolism
(metabolomics) is now
being revisited as an attractive target.

One such regulatory approach is via the manipulation of cellular energy. Cellular energy is synonymous with metabolic power. As we age there is a decrease in metabolism, furthermore, numerous disease states involve metabolic dysfunction (i.e. ischemia/stroke, cancer).
As all scientists know, the major power plant of the cell is the mitochondria. It utilizes high energy intermediates (NADH and FADH) to donate electrons and drive the production of ATP, our functional energy source.

As noted throughout this website, the most recent research is focused on finding compounds that effectively improve metabolic activity by providing an alternative electron source for each cell in the body? (see graphic to the left)

Cellular metabolism is critical for providing the energy for genes and proteins to be made, which subsequently influences the metabolic rate of a cell. Without the proper levels of energy, errors in gene and protein transcription can occur.
How important are Cellular Energy & Mitochondrial Function?

Very Low energy levels = Possible Genetic Errors
Normal energy levels = Proper Gene & Protein Transcription

Metabolic dysfunction as a result of Mitochondrial Dysfunction is at the heart of a multitude of clinical conditions, including cancer. The approach of implementing products or compounds that increase or maintain mitochondrial function thereby combatting metabolic dysfunction can be viewed as a metabolically targeted therapy (MTT).
Metabolically Targeted Therapy (MTT)
One example of a metabolically targeted therapy (MTT) is a new proprietary product line called Mito~Direct™. These formulations are designed to transport Electrons(energy), Vitamins, Minerals and key Nutrients directly to intracellular mitochondria. As is the case with many inferior supplements, if these nutrients are unable to be absorbed across the intestinal wall and cross the cell membrane and enter the cell, they can not provide the body any physiological or nutritional benefit.

This critical delivery system is carried out by key nutrients that act as a redox polymers. Redox polymers more efficiently accept and donate charge, compared to single molecules. This direct delivery of nutrients and electrons (directly to mitochondria residing within each cell) allows Mito~Direct formulations to serve as an energy source for mitochondrial ATP production thereby reversing Hypoxia and Mitochondrial Dysfunction(see research below).
Has Clinical Research been looking
in the wrong place for the past 50 years?

The 3rd party clinical studies found on this site suggest an emphatic,

After reading the 3rd party peer reviewed articles listed below and posted throughout this website, one central theme becomes clear.
 "Mitochondrial dysfunction has been implicated in
nearly all pathologic and toxicologic conditions."
Experimental and Molecular Pathology
Volume 83, Issue 1, August 2007, Pages 84-92

10 Chronic Diseases linked to mitochondrial dysfunction
During hypoxia, the HIF-1 gene turns on hypoxic dependent genes
and represses or turns off normoxic dependent genes
The latest research suggests that the Human Cell contains as many as 20,000 different genes but only a fraction of these genes are turned on at one time.

When proper oxygen levels are available under normoxic conditions, hypoxic genes, like HIF-1, are repressed, or turned off resulting in the homeostasis of a healthy cell and normal mitochondrial function.
However, when a cell becomes hypoxic, HIF-1 levels and other hypoxic dependent genes are transcribed resulting in a disease state within the cell. Increased HIF-1 levels results in the downstream transcription of Vascular Endothelial Growth Factor (VEGF) – a promoter of angiogenesis; Glucose Transport 1 (GLUT1) and glycolytic enzymescritical components in anaerobic respiration; and Erythropoietin (EPO) – responsible for the differentiation of red blood cells. (supporting article:  Free Radic Biol Med. 2009 Jan)

The transcription of these hypoxic dependent genes would have never occurred if the cell had remained under normoxic conditions.
This cellular response to low oxygen, or hypoxia, involves the regulation of many cellular pathways that shut down low priority cellular activity and increase stress responses.
These signals from the environment during hypoxia activate various proteins which are called transcription factors. These proteins bind to regulatory regions of a gene and increase or decrease the level of transcription. By controlling the level of transcription, this process can determine the amount of protein product that is made by a gene at any given time.

Why have scientists spent the last 50 years trying to repair genes AFTER the cell has entered the disease state when
the cause of their dysfunction is now known to be hypoxia and oxidative stress caused by mitochondrial dysfunction?

Wouldn't it make more sense to implement strategies to prevent hypoxia & reverse oxidative stress thereby preventing
the transcription of each of these hypoxic dependent genes
that lead to a disease state within the cell?

Why are these same scientists suggesting that disease is based on GENETIC ERRORS when most of these errors
occur due to the transcription of genes that are only turned on under hypoxic conditions!

If mitochondrial dysfunction leads to oxidative stress & the upregulation of HIF-1, wouldn't it make sense
to develop a compound that can reverse this dysfunction and prevents hypoxia.
Oxidative Stress, upregulation of HIF-1 and Mitochondrial Dysfunction
Most causes of mitochondrial dysfunction tend to involve oxidative stress which can be generated by a myriad of sources. These levels of oxidative stress can be dramatically increased and persist at dangerous levels if the human body is continually exposed to more than 1 of the following sources at the same time......see list below.
Exposure to these sources
can lead to Mitochondrial Dysfunction
alcohol, artificial trans fats, aspirin, excess calories, glucocorticoids, homocysteine, iron overload, lipid peroxidation, lipopolysaccharide, MSG, nutrient deficiencies, oxidized LDL, pro-inflammatory cytokines, prescription drugs, sleep deprivation, smoking, statins and toxic heavy metals.

Per the published studies found on this website, the human body is constantly exposed to many of these known causative factors resulting in Oxidative stress and the upregulation of HIF-1. As noted in the article below from Johns Hopkins, if this dysfunction is not reversed, it is only a matter of time before this long term oxidative stress will manifest itself in disease and suffering.
The Johns Hopkins report below states that HIF-1 is a genetic switch that SHUTS DOWN Mitochondrial function to protect the cell from producing ROS which would result in the overproduction of Oxygen Radicals. In an ironic twist, HIF-1 protects the cell from damage or cell death by shutting down the whole system thereby preventing futher mitochondrial ROS production.
The formulation goal of  Mito~Direct Complexes is to support HYPOXIC CELLS and downregulate and/or attenuate HIF-1 levels.  By reversing HIF-1 levels and oxidative stress, users can reverse hypoxia and cellular dysfunction. Not only are  Mito~Direct™ Complexes designed to reverse HIF-1 levels, they are also designed to help to deliver a constant supply of electrons directly to the mitochondria in order to maintain ATP production. This feature is the textbook example of how Mito~Direct™ Complexes rescue cells from the damaging effects of hypoxia associated with HIF-1.

Hopkins researchers discover unsuspected
genetic switch(HIF-1) that turns off Mitochondria

HIF-1 suppresses mitochondrial function
A cell’s energy demands are met by two major types of sugar ( glucose) using machines similar to the two types of engines in a hybrid car.  One machine, the mitochondrion, is an organelle that breaks down the glucose-using oxygen and produces ATP. The other  does the same thing - albeit less efficiently - without using oxygen in a process called glycolysis.

Like the hybrid car, cells  use oxygen and the internal combustion engine at higher speeds and rely on an electric engine without need for oxygen consumption at lower speeds. Cells consume glucose through its main energy-producing machine, the mitochondrion, when oxygen is ample.  But like the internal combustion engine, this process generates pollutants or toxic oxygen molecules.
At lower oxygen levels, when cells are starved for oxygen - as during exertion or trauma --  the genetic switch that the Hopkins researchers found  deliberately shuts off the cell’s mitochondrial combustion engine, which scientists had long - and erroneously --  believed ran down on its own due to lack of oxygen.
“The unexpected discovery is that this genetic switch actively shuts off the mitochondrion under low oxygen conditions, apparently to protect cells from mitochondrial toxic oxygen pollutants,” said Chi Van Dang, M.D., Ph.D., professor of medicine, cell biology, oncology and pathology, and vice dean for research at the Johns Hopkins University  School of Medicine.

Dang says the switch may be a target for cancer drugs because a cancer cell’s survival depends on it to convert glucose to lactic acid through glycolysis even in the presence of ample oxygen. Disruption of the switch(HIF-1) by a drug may cause cancer cells to pollute themselves with toxic oxygen molecules and undergo apoptosis or cell death.

The disruption of this link blocks the tendency of the mitochondrion to make toxic molecules as it struggles to produce ATP during hypoxia. These toxic molecules, called reactive oxygen species (ROS), damage molecules in the cell and even cause the cell to undergo apoptosis.
"But our discovery clearly shows that hypoxia doesn’t simply trigger a passive shutdown of the mitochondrion,” said Dang. “Instead, HIF-1 acts as a genetic switch to actively shut down mitochondrial function and prevent the production of reactive oxygen species.”
Read full article here
Free Radic Biol Med. 2009 Jan
Relationship between oxidative stress and HIF-1 alpha
mRNA during sustained hypoxia in humans.
The aim of this study was to investigate the relations among reactive oxygen species (ROS), hypoxia inducible factor (HIF-1 alpha) gene expression, HIF-1 alpha target gene erythropoietin (EPO), and vascular endothelium growth factor (VEGF) in humans. Five healthy men (32+/-7 years, mean+/-SD) were exposed to 12 h of sustained poikilocapnic hypoxia (P(ET)O(2)=60 mmHg).

DNA oxidation (8-hydroxy-2'-deoxyguanosine, 8-OHdG), advanced oxidation protein products (AOPP), EPO, and VEGF were measured in plasma and HIF-1 alpha mRNA was assessed in leukocytes before and after 1, 2, 4, 6, 8, 10, and 12 h of exposure to hypoxia. HIF-1 alpha mRNA amount increased during the first two hours of hypoxic exposure and then returned to baseline levels. The findings reveal an up-regulation of HIF-1 alpha (+68%), VEGF (+46%), and EPO (+74%). AOPP increased continuously from 4 h (+69%) to 12 h (+216%) of hypoxic exposure while 8-OHdG increased after 6 h (+78%) and remained elevated until 12 h.

During the "acute" increase phase of HIF-1 alpha (between 0 and 2 h), 8-OHdG was positively correlated with HIF-1 alpha (r=0.55). These findings suggest that hypoxia induces oxidative stress via an overgeneration of reactive oxygen species (ROS).

Finally, this study in humans corroborates the previous in vitro findings demonstrating that
ROS is involved in HIF-1 alpha transcription.

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