Mitochondrial diseases

Pharmaceutical biology

Viktor Soma Poór

 Mitochondrial genetics
• Every cells contains a lot of mitochondria, each
containing many copies of 16.5 kb circular
mtDNA.
• It features:
– DNA replication is independent from S phase
– lack of histones
– lack of introns
– both chains are transcribed
– no 5’ cap at the mRNA
– coding different tRNAs
The mutation rate of mtDNA is higher
than the genomic DNA
• lack of histone proteins
• low activity proofreading of DNA polymerase γ
• reactive oxygen species
 Heteroplasmy/homoplasmy
• Homoplasmy: all the mtDNA share the same
sequence in the cell
• Heteroplasmy: more than one sequences are
present
– threshold limit: the ratio of defected mtDNA when
the symptoms appear
Heteroplasmy
Homoplasmy

X X
 Heteroplasmy/homoplasmy
• Homoplasmy: all the mtDNA share the same
sequence in the cell
• Heteroplasmy: more than one sequences are
present
– threshold limit: the ratio of defected mtDNA when
the symptoms appear
Heteroplasmy
Homoplasmy

X X
 Mitochondrial diseases
• heterogeneous diseases with usually no
characteristic syndromes
• low efficiency of ATP synthesis in the affected
organs
• act on organs with high energy consumption:
– central nervous system
– heart muscle
– skeletal muscles
– optic nerve
 Typical symptoms
• Ataxia
• Myopathy
• Cardiomyopathy
• Seizures
• Deafness
• Lactic acidosis
Inheritance pattern of mitochondrial
diseases
 Classification of mt diseases
• Mutation in the mtDNA
– Inherited mitochondrial diseases
– Acquired mitochondrial diseases
• Mutation in the nuclear DNA
 Inherited mitochondrial diseases
• Germ cell (oocyte) carries the mutation
• Maternal inheritance
• heteroplasmy/homoplasmy
Leber’s hereditary optic neuropathy
(LHON)
 Leber’s hereditary optic neuropathy
(LHON)
• The first identified mitochondrial disease
• mutation in the genes coding NADH
dehydrogenase
• acute onset visual loss
• bilateral
• onset is usually young adulthood
 Myoclonic Epilepsy with Ragged Red
Fibers (MERRF)
• Mutation of gene for tRNA-Lys
• Symptoms:
– myoclonic epilepsy
– ragged red fibres
– hearing loss
– lactic acidosis
 Ragged Red fibres

Diseased mitochondria accumulate in the

subsarcolemmal region
 Leigh’s disease
• Necrotizing Encephalomyelopathy
• early onset: 3 months – 2 years
• mtDNA or nuclear DNA mutation
• Symptoms:
– movement disorders
– seizures
– lactic acidosis
 Acquired mitochondrial disorders
• Somatic mtDNA mutation
• Heteroplasmy
• Can be caused by drugs (e.g. AZT,
azidothymidin)
• Found in certain types of diabetes mellitus,
Parkinson's disease, Alzheimer’s disease
 Mitochondrial disorders caused by
nuclear mutations
• Many of the mitochondrial proteins are coded
by the nuclear DNA
• disturbances in ATP synthesis
• Mendelian inheritance (not maternal!!)
 Diagnostic possibilities
• sequencing the suspected part of mtDNA after
setting up the primary diagnosis
• isolate the mtDNA from the affected organs in
the case of acquired mutations!
 Therapeutic possibilities
• Currently there are no cures for mitochondrial
diseases
• treatment of symptoms (supplement)
• For PHARMACISTS!: some medications must
be avoided! (e.g. ethambutol triggers LHON)
 Coenzyme Q10
• Shuttling electrons from complexes I or II
• In some mitochondrial diseases it is effective
• Low solubility in water
• Short half-life
 Riboflavin (B2)
• It is a key building block in complex I and II
and a cofactor in several other key enzymatic
reactions involving fatty acid oxidation and the
Krebs cycle.
• Slows progression, amelioration of symptoms.
 L-creatine
• Source of high-energy phosphate, released
during anaerobic metabolism.
• Treatment resulted in an increase in high-
intensity, isometric, anaerobic, and aerobic
power.
• No effects were observed on aerobic cycle-
ergometry exercise variables, body
composition, 2-minute walk, or activity of
daily living scores.
 L-carnitine
• Transfers long-chain fatty acids across the
mitochondrial inner membrane as
acylcarnitine esters.
• No studies have confirmed a benefit of
isolated use of carnitine in patients with
primary mitochondrial disorders.
 Assistive devices
• Cochlear implants
• Cardiac pacemakers and defibrillators
 Drugs with reported mitochondrial toxicity
Medication Symptoms Mechanism
Valproic acid Hepatopathy; infrequently direct Inhibition of fatty acid oxidation, the
encephalopathy citric acid cycle, and oxidative
phosphorylation; carnitine depletion;
complex IV inhibition
(contraindicated in mitochondria
depletion syndromes)
Antiretrovirals Peripheral neuropathy, liver dysfunction, Impairment of mtDNA replication
myopathy causing mtDNA depletion; carnitine
deficiency, lactic acidosis,
lipodystrophy
Statins Myopathy Multiple postulated effects, including
CoQ10 depletion
Aspirin Reye syndrome Inhibition and uncoupling of oxidative
phosphorylation
Aminoglycoside antibiotics Hearing loss, cardiac toxicity, renal toxicity Impaired mtDNA translation

Aminoglycoside and platinum Hearing loss, cardiac toxicity, renal toxicity Impaired mtDNA translation
chemotherapeutics
Acetaminophen Hepatopathy Oxidative stress
Metformin Lactic acidosis Inhibition of oxidative
phosphorylation, enhanced glycolysis
Beta-blockers Reduced exercise tolerance Oxidative stress
Steroids Reports of deterioration in Kearns-Sayre Unknown
syndrome
Prevention of inheritance: pronuclear
transfusion
Alana Saarinen, the girl with three
parents
 The minimum
• Mitochondrial genetics, mitochondrial
inheritance
• The causes of high mutation rate of mtDNA
• Characteristics of mitochondrial diseases
• Examples for inherited mitochondrial diseases