From Alzheimer’s to Zebrafish: Eclectic Science and Regulatory Stories 116
on is shown by the fact that at any instant, each cell contains about 1,000,000,000 ATP
molecules.16
In terms of structure, mitochondria have an outer lipid membrane as well as an
inner one, and each fusion event requires the coordinated fusion of the membranes.17
All animals contain at least some mitochondria even sessile plants and algae use them
to augment the solar energy derived from photosynthesis.18 Mitochondria are indepen-
dent in that they have their own genetic makeup, unrelated to that of the cell, and their
own ribosomes. (Ribosomes are the protein-building factories located in the cytoplasm.)
Mitochondria reproduce on their own. Surprisingly, mitochondrial DNA has but 37 genes
and few of them account for its energy-producing function.19 As a comparison, the esti-
mate for the number of genes in humans has decreased as our knowledge has increased,
from 100,000 to perhaps as few as 20,000, with 25,000 now a commonly accepted number.20
Most, or 95%, of these genes appear to be involved in less-well-defined duties, telling the
cell how to build, break down and recycle proteins, the workhorses of life. Mitochondria
are also involved in other processes, such as signaling, cellular differentiation and control
of the cell’s lifecycle.21
Mitochondrial Diseases
Mitochondrial diseases result from failures of the mitochondria and cause damage to
cells of the brain, heart, liver, skeletal muscles, kidney, eyes, the gastrointestinal tract
and the endocrine and respiratory systems.22 More precisely, these diseases result from
dysfunction of the mitochondrial oxidative phosphorylation (OXPHOS) system, which is
composed of the four enzyme complexes of the electron transport respiratory chain, and
of ATP synthase, which uses the proton gradient generated by the electron transport chain
to produce ATP.23 As all of the organs of the body rely on ATP generated by OXPHOS for
their normal function, impairment of this system can affect any organ system, making
diagnosis particularly difficult. Tissues with high basal energy requirements, however,
are extremely susceptible to the energy failure that occurs in mitochondrial diseases.24
They include tissues that are highly dependent on oxidative metabolism, such as the
brain, heart, skeletal muscle, retina, renal tubules and endocrine glands. These tissues
are especially vulnerable to the effects of pathogenic mutations in mitochondrial DNA
(mtDNA).25 Examples of diseases due to mutations that impair mitochondrial protein
synthesis include progressive external ophthalmoplegia, Pearson and Leigh syndromes
and mitochondrial encephalomyopathy. Diseases due to mutations in protein coding
genes include Leber hereditary optic myopathy, cardiomyopathy and myoclonus epilepsy
with ragged red fibers. Most mtDNA-related diseases share a number of features includ-
ing lactic acidosis and massive mitochondrial proliferation in muscle tissue. Moreover,
mitochondrial diseases are not as rare as commonly believed their estimated prevalence
of 10 to 15 cases per 100,000 people is similar to that of better-known neurological diseases
such as amyotrophic lateral sclerosis and the muscular dystrophies.26 It is fair to say that
the role of mitochondria in human disease has exceeded all expectations.27
Treatment
Even though there has been some success, and progress has been made in understand-
ing the biochemical and molecular bases for mitochondrial diseases, medical science is
still limited in its ability to treat them.28 Development of and experimentation with new
therapies is made more difficult by the lack of spontaneous or engineered animal mod-
els. Rational therapies remain elusive in the absence of a clear understanding of basic
pathogenic mechanisms. As a general rule, those with mild disease tend to respond to
treatment better than those with severe disorders. Current treatment has been palliative
and includes the indiscriminate use of vitamins (riboflavin and thiamine), cofactors (Co-Q
10 and levo-creatine) and oxygen radical scavengers such as vitamin E.29 Fortunately, in
on is shown by the fact that at any instant, each cell contains about 1,000,000,000 ATP
molecules.16
In terms of structure, mitochondria have an outer lipid membrane as well as an
inner one, and each fusion event requires the coordinated fusion of the membranes.17
All animals contain at least some mitochondria even sessile plants and algae use them
to augment the solar energy derived from photosynthesis.18 Mitochondria are indepen-
dent in that they have their own genetic makeup, unrelated to that of the cell, and their
own ribosomes. (Ribosomes are the protein-building factories located in the cytoplasm.)
Mitochondria reproduce on their own. Surprisingly, mitochondrial DNA has but 37 genes
and few of them account for its energy-producing function.19 As a comparison, the esti-
mate for the number of genes in humans has decreased as our knowledge has increased,
from 100,000 to perhaps as few as 20,000, with 25,000 now a commonly accepted number.20
Most, or 95%, of these genes appear to be involved in less-well-defined duties, telling the
cell how to build, break down and recycle proteins, the workhorses of life. Mitochondria
are also involved in other processes, such as signaling, cellular differentiation and control
of the cell’s lifecycle.21
Mitochondrial Diseases
Mitochondrial diseases result from failures of the mitochondria and cause damage to
cells of the brain, heart, liver, skeletal muscles, kidney, eyes, the gastrointestinal tract
and the endocrine and respiratory systems.22 More precisely, these diseases result from
dysfunction of the mitochondrial oxidative phosphorylation (OXPHOS) system, which is
composed of the four enzyme complexes of the electron transport respiratory chain, and
of ATP synthase, which uses the proton gradient generated by the electron transport chain
to produce ATP.23 As all of the organs of the body rely on ATP generated by OXPHOS for
their normal function, impairment of this system can affect any organ system, making
diagnosis particularly difficult. Tissues with high basal energy requirements, however,
are extremely susceptible to the energy failure that occurs in mitochondrial diseases.24
They include tissues that are highly dependent on oxidative metabolism, such as the
brain, heart, skeletal muscle, retina, renal tubules and endocrine glands. These tissues
are especially vulnerable to the effects of pathogenic mutations in mitochondrial DNA
(mtDNA).25 Examples of diseases due to mutations that impair mitochondrial protein
synthesis include progressive external ophthalmoplegia, Pearson and Leigh syndromes
and mitochondrial encephalomyopathy. Diseases due to mutations in protein coding
genes include Leber hereditary optic myopathy, cardiomyopathy and myoclonus epilepsy
with ragged red fibers. Most mtDNA-related diseases share a number of features includ-
ing lactic acidosis and massive mitochondrial proliferation in muscle tissue. Moreover,
mitochondrial diseases are not as rare as commonly believed their estimated prevalence
of 10 to 15 cases per 100,000 people is similar to that of better-known neurological diseases
such as amyotrophic lateral sclerosis and the muscular dystrophies.26 It is fair to say that
the role of mitochondria in human disease has exceeded all expectations.27
Treatment
Even though there has been some success, and progress has been made in understand-
ing the biochemical and molecular bases for mitochondrial diseases, medical science is
still limited in its ability to treat them.28 Development of and experimentation with new
therapies is made more difficult by the lack of spontaneous or engineered animal mod-
els. Rational therapies remain elusive in the absence of a clear understanding of basic
pathogenic mechanisms. As a general rule, those with mild disease tend to respond to
treatment better than those with severe disorders. Current treatment has been palliative
and includes the indiscriminate use of vitamins (riboflavin and thiamine), cofactors (Co-Q
10 and levo-creatine) and oxygen radical scavengers such as vitamin E.29 Fortunately, in