What you need to know about
Mitochondria
.
| |
|
Symptoms
Symptoms include poor growth, loss of muscle
coordination, muscle weakness, visual problems, hearing
problems, learning disabilities, heart disease, liver
disease, kidney disease, gastrointestinal disorders,
respiratory disorders, neurological problems, autonomic
dysfunction and dementia.
Characteristics
The effects of mitochondrial disease can be quite
varied. Since the distribution of the defective
mitochondrial DNA may vary from organ to organ within
the body, and each mutation is modulated by other genome
variants, the mutation that in one individual may cause
liver disease might in another person cause a brain
disorder. The severity of the specific defect may also
be great or small. Some minor defects cause only
"exercise intolerance", with no serious illness or
disability. Defects often affect the operation of the
mitochondria and multiple tissues more severely, leading
to multi-system diseases.
Mitochondrial diseases as a rule are worse when the
defective mitochondria are present in the muscles,
cerebrum, or nerves, because these cells use more energy
than most other cells in the body. Although
mitochondrial diseases vary greatly in presentation from
person to person, several major clinical categories of
these conditions have been defined, based on the most
common phenotypic features, symptoms, and signs
associated with the particular mutations that tend to
cause them.
An outstanding question and area of research is whether
ATP depletion or reactive oxygen species are in fact
responsible for the observed phenotypic consequences.
The research on this website supports this hypothesis.
Causes
Mitochondrial disorders may be caused by mutations,
acquired or inherited, in mitochondrial DNA (mtDNA) or
in nuclear genes that code for mitochondrial components.
They may also be the result of acquired mitochondrial
dysfunction due to adverse effects of drugs, infections,
or other environmental causes.
Nuclear DNA has two copies per cell (except for sperm
and egg cells), one copy being inherited from the father
and the other from the mother. Mitochondrial DNA,
however, is strictly inherited from the mother and each
mitochondrial organelle typically contains multiple
mtDNA copies. During cell division the mitochondrial DNA
copies segregate randomly between the two new
mitochondria, and then those new mitochondria make more
copies. If only a few of the mtDNA copies inherited from
the mother are defective, mitochondrial division may
cause most of the defective copies to end up in just one
of the new mitochondria. Mitochondrial disease may
become clinically apparent once the number of affected
mitochondria reaches a certain level; this phenomenon is
called "threshold expression".
Mitochondrial DNA mutations occur frequently, due to the
lack of the error checking capability that nuclear DNA
has (see Mutation rate). This means that mitochondrial
DNA disorders may occur spontaneously and relatively
often. Defects in enzymes that control mitochondrial DNA
replication (all of which are encoded for by genes in
the nuclear DNA) may also cause mitochondrial DNA
mutations.
Most mitochondrial function and biogenesis is controlled
by nuclear DNA. Human mitochondrial DNA encodes only 13
proteins of the respiratory chain, while most of the
estimated 1,500 proteins and components targeted to
mitochondria are nuclear-encoded. Defects in
nuclear-encoded mitochondrial genes are associated with
hundreds of clinical disease phenotypes including
anemia, dementia, hypertension, lymphoma, retinopathy,
seizures, and neuro-developmental disorders.
Treatment
Although research is ongoing, treatment options are
currently limited; vitamins are frequently prescribed,
though the evidence for their effectiveness is limited.
Membrane penetrating antioxidants have the most
important role in improving mitochondrial dysfunction.
Spindle transfer, where the nuclear DNA is transferred
to another healthy egg cell leaving the defective
mitochondrial DNA behind, is a potential treatment
procedure that has been successfully carried out on
monkeys Using a similar pronuclear transfer technique,
researchers at Newcastle University successfully
transplanted healthy DNA in human eggs from women with
mitochondrial disease into the eggs of women donors who
were unaffected. In September 2012 a public consultation
was launched in the UK to explore the ethical issues
involved. Human genetic engineering is already being
used on a small scale to allow infertile women with
genetic defects in their mitochondria to have children.
Statistics
About 1 in 4,000 children in the United States will
develop mitochondrial disease by the age of 10 years. Up
to 4,000 children per year in the US are born with a
type of mitochondrial disease. Because mitochondrial
disorders contain many variations and subsets, some
particular mitochondrial disorders are very rare.
Many diseases of aging are caused by defects in
mitochondrial function. Since the mitochondria are
responsible for processing oxygen and converting
substances from the foods we eat into energy for
essential cellular functions, if there are problems with
the mitochondria, it can lead to many defects for
adults. These include Type 2 diabetes, Parkinson's
disease, atherosclerotic heart disease, stroke,
Alzheimer's disease, and cancer.
Many medicines can also injure the mitochondria as noted
in the clinical study below.
|
| |
| |
| |
|
|
| |
| |
Prescribed Drugs
are a major cause of Mitochondrial damage
.
|
Molecular Nutrition & Food
Research
|
Medication-induced mitochondrial damage and
disease
John Neustadt, Steve R. Pieczenik
Published: July 14, 2008
|
|
| |
|
Abstract
Since the first mitochondrial dysfunction was described in
the 1960s, the medicine has advanced in its understanding
the role mitochondria play in health and disease.
Damage to mitochondria is now understood to play a role in
the pathogenesis of 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.
Medications have now emerged as a
major cause of mitochondrial damage,
which may explain many adverse effects. All classes
of psychotropic drugs have been documented to damage
mitochondria, as have statin medications,
analgesics such as acetaminophen, and
many others.
While targeted nutrient
therapies using antioxidants or their
prescursors (e. g., N-acetylcysteine)
hold promise for improving mitochondrial function,
there are large gaps in our knowledge. The most
rational approach is to understand the mechanisms underlying
mitochondrial damage for specific medications and attempt to
counteract their deleterious effects with nutritional
therapies. This article reviews our basic
understanding of how mitochondria function and
how medications damage mitochondria to
create their occasionally fatal adverse effects.
|
| |
| |
|
Overview
and List of Drugs that
damage Mitochondria
.
Mechanisms of Action
Anything can be toxic if it inhibits the electron
transport chain. Oxidative-phosphorylation disease
is affected by any disruption in the ETC. What
appears to be a necessity , ie, oxygen, can in
itself be damaging. There are many ways that free
radicals can be formed and these free oxygen
radicals can be toxins if not handled appropriately.
Free radical damage can cause increased energy needs
with a cascading effect of further damage. The key
is to attempt to balance the treatment needs with
the side effects of the treatment.
The pathobiology of mitochondrial toxicity is not
well understood. Toxicity may be exacerbated by
other problems and treatments, so always be watchful
and observant of all symptoms. Mitochondrial
function needs to be supported, not impeded. The
types of toxic agents include: pharmaceutical
products (medications), anesthesia, surgery,
environmental agents, diet, stress related
endogenous agents, and mitochondrial cofactors. A
table of the various agents discussed here will be
included as an attachment to this summary.
Pharmaceutical products
Establishing mitochondrial toxicity is not an FDA
requirement for drug approval, so there is no real
way of knowing which agents are truly toxic. Nor is
there an absolute contraindication against any
particular agent, BUT there are those that we know
should be avoided. Some agents have been shown
(either through research studies or anecdotal
evidence) to have direct toxicity to the
mitochondria. These agents directly inhibit or
disrupt the ETC, protein production, DNA
transcription, etc. Agents that cause indirect
toxicity are those that increase free radicals,
decrease the production of endogenous antioxidants,
or deplete nutrients that are needed.
Anticonvulsants
Specifically, most anticonvulsants are well
tolerated except valproate (Depakote). This drug
can inhibit many mitochondrial functions. It is
known to play important role in carnitine
utilization by the mitochondria and has been shown
to particularly inhibit complex IV. It can also
cause liver dysfunction. This does not mean it
should never be used, but caution needs to be taken
regarding liver function. If used, plasma carnitine
levels need to be monitored and maintained
carefully.
Psychotropics
Certain psychotrophic drugs have been shown to be
potentially toxic. Certain antidepressants such as
Prozac, Elavil, and Cipramil can cause autonomic
dysfunction. Other psychotropic drugs such as
antipsychotics, barbituates, and antianxiety
medications also inhibit various mitochondrial
functions.
Cholesterol Medications
Cholesterol lowering drugs (especially statins) have
been shown to reduce endogenous CoEnzynme Q10 is
produced in the same metabolic pathway as
cholesterol, so in this way these drugs can be said
to be potentially toxic. Other cholesterol
medications such as cholestyramine that bind to bile
acids can distrupt the ETC.
Analgesics and Anti-inflammatories
Pain relievers such as acetimenophen (sp?), Indocin,
naproxen, Aspirin and the NSAIDS (non steriodal anti
inflammatory drugs), all increase oxidative stress,
and therefore could potentially be toxic. Aspirin is
contraindicated for children, but it can be harmful
for patients with mitochondrial disease as well
because of the potential for Reye Syndrome (acute
liverfailure). However, patients should keep in mind
that it is important to avoid fevers in Mito
patients. Therefore, the benefits of some of these
medications as fever-reducers may outweigh their
potential side-effects.
Antibiotics
Antibiotics, (specifically tetracycline, minocycline,
chloramphenical, and aminoglycosides), can be
harmful to the mitochondria because they inhibit
mtDNA translation and protein synthesis. They can
cause hearing loss as well as cardiac and renal
toxicity.
Steroids
Steroids may reduce transmembrane mitochondrial
potential. However, steroids used in local delivery
(such as inhaled steroids that only target lungs or
injected steroids that target specific locations)
are generally recognized as safe.
Other drugs which are used less by the Mito
population but have potential toxicity include
amiodarone which is used as an
anti-arrhythmic (rapid heart rate), antivirals like
interferon, antiretrovirals
(used for HIV/AIDS), and cancer drugs.
Metformin, used for diabetes, is
also considered toxic to mitochondria.
Beta blockers could have possible
toxicity due to increased oxidative stress, and may
also contribute to feelings of fatigue.
Diuretics are usually not harmful
to the mitochondria themselves, but they may cause
fluid imbalances.
In all cases of the drugs mentioned here, the
objective is to balance the need for use of these
drugs with the damage they may cause.
Anesthesia
In mitochondrial disease, there seems to be an
increased sensitivity to anesthesia, especially the
volatile drugs (ie, those inhaled). For this reason,
there should be very close management of any
anesthesia used even when IV (for example,
propofal). Often a decreased dosage is
adequate. The smallest dose over the shortest
period of time should be the goal of all anesthesia
for mitochondrial disease patients. Patients with
mitochondrial diseases should make sure that their
anesthesiologist is informed and knowledgeable about
their condition so that they use the upmost caution
and safety while using anesthetics.
|
|
|
| |
| |
|
|
| |
| |
|
Mitochondrial
dysfunction implicated in nearly all diseases
. |
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
|
|
| |
Abstract
"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."
|
| |
| |
|
|
|
