Background and Opportunity
The Critical Role of Mitochondria in Human Health and Disease
Mitochondria are specialized cellular substructures that are essential to human life. They utilize more than 90% of inhaled oxygen, generate nearly all of the cell's energy and participate in many cellular pathways, including metabolism and cell death. Mitochondria are essential to cell growth and function because they convert carbohydrates, fats and proteins from food into the body's principal form of energy, adenosine triphosphate, or ATP. The biological process that creates ATP involves a series of mitochondrial protein complexes known as the electron transport chain. The tissues of the body that rely most heavily on mitochondria are composed of long-lived, energy demanding cell types, like those found in the brain, muscles and the pancreas. As a result, mitochondrial dysfunction has a significant impact on these tissues.
If the supply of ATP is disrupted, or if mitochondrial activity declines below levels required to sustain normal cellular processes, tissue function can be compromised, threatening a person's health. Even a brief interruption in the supply of oxygen to certain tissues can lead to a rapid depletion of mitochondrial energy levels, resulting in cell injury that can ultimately trigger cell death. One consequence of mitochondrial failure is a form of cell death called apoptosis, which mitochondria initiate by releasing specific cell death-activating proteins. Mitochondria are also the primary cellular source of highly reactive molecules called free radicals that cause cellular stress and can induce apoptosis. Impairment of mitochondrial function can lead to age-related degenerative diseases by weakening cell membranes, increasing the demand for cellular energy and undermining the integrity of the genome.
The Mitochondrial Genome
In humans, mitochondria are the only parts of the cell other than the nucleus that contain their own genomes. In contrast to the nuclear genome, which has been the focus of so much recent study, the mitochondrial genome is inherited only from the mother. At 16,569 base pairs, the mitochondrial genome is smaller and easier to analyze than the three billion base pairs that comprise the nuclear genome. Both genomes contain instructions, or codes, for mitochondrial proteins, and as a result, proper mitochondrial structure, growth and function depend on the
35
--------------------------------------------------------------------------------
coordinated expression of genes in both the nucleus and mitochondria. Based on various studies published in Electrophoresis and A Primary Care Physician's Guide, we estimate that nuclear genes code for approximately 2,000 mitochondrial proteins, the majority of which have not been well characterized. Alterations in any mitochondrial gene or protein may undermine mitochondrial and cellular viability, so understanding the mitochondrial genome and proteome can provide new avenues for studying, diagnosing and treating disease.
The mitochondrial genome is particularly vulnerable to genetic alterations, partially because of its proximity to the harsh environment of mitochondrial metabolism, but also because according to articles in Nature more than 90% of the DNA in the mitochondrial genome codes for proteins and ribonucleic acids, or RNAs. In marked contrast to the nuclear genome, the occurrence of non-coding, or "junk," DNA in the human mitochondrial genome is minimal. In the American Journal of Human Genetics, the mitochondrial genome is estimated to be 10 to 20 times more variable than nuclear DNA sequences. As a result, mitochondrial mutations are more common and more likely to have detrimental effects on cellular function. Mitochondrial diseases may result from alterations in mitochondrial genes or proteins, from alterations in nuclear genes or proteins, from a combination of changes or from more complex mechanisms including the detrimental effects of environmental toxins.
Market Opportunity for Mitochondrial Medicine
Due to the critical role of mitochondria in so many aspects of cellular function, more than 75 diseases have been linked directly or indirectly to mitochondrial dysfunction. Mitochondrial dysfunction may be an inevitable part of the aging process, resulting from a combination of inherited and acquired genetic and functional defects. We believe that the increasing average age of the general population, coupled with a more developed understanding of mitochondria, will give mitochondrial medicine an increasingly important and expanding role in healthcare. The following table sets forth the market opportunities for mitochondrial medicine in the immediate and longer terms, as well as selected diseases and conditions with mitochondrial links, their representative symptoms and mitochondrial mechanisms and pathways.
36
--------------------------------------------------------------------------------
--------------------------------------------------------------------------------
Market Opportunities for • Drug candidates for major diseases
Mitochondrial Medicine • Identification of new proteins for use in drug discovery
• Disease-relevant models
• High-throughput screens and high-content assays for drug discovery and methods of assessing potential drug toxicity (MitoMetrics)
• Human gene and protein databases and bioinformatics software
• Customized libraries of chemical compounds used in drug discovery
• Drug delivery approaches
• Diagnostic markers and research tools
--------------------------------------------------------------------------------
Diseases and Conditions with • Alzheimer's disease
Mitochondrial Links • Parkinson's disease
• Stroke
• Obesity
• Type II diabetes
• Osteoarthritis
• Glaucoma
• Friedreich's ataxia
• Cancer
• Other degenerative conditions associated with aging
--------------------------------------------------------------------------------
Symptoms Associated with • Neurodegeneration
Mitochondrial Dysfunction • Neurological disorders including seizures
• Learning disabilities, developmental delays and retardation
• Susceptibility to infection
• Liver and kidney problems
• Insulin and glucose imbalances and diabetic complications
• Respiratory problems
• Gastrointestinal disorders
• Cardiovascular problems, including heart failure
• Visual and hearing deficits, including optic neuropathy, retinal degeneration and deafness
• Loss of motor control, muscle weakness and skeletomuscular abnormalities
• Poor growth
--------------------------------------------------------------------------------
Mitochondrial Mechanisms • Bioenergetic and metabolic failure
and Pathways • Cellular stress and damage from free radicals
• Cell death pathways, including apoptosis
• Mitochondrial, nuclear, or combined mitochondrial and nuclear DNA alterations
• Variations in DNA sequence referred to as single nucleotide polymorphisms, or SNPs
• Sets of ethnically related SNPs called haplogroups or haplotypes
• DNA deletions or repeats
• Other mutations |
