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    Mitochondrial Diseases

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    Ali Mansor
    Mitochondrial diseases can be caused by mutations in mitochondrial DNA or nuclear DNA. mtDNA has a higher mutation rate than nuclear DNA due to lack of histones, DNA polymerase proofreading errors, and reactive oxygen species damage. Mitochondrial diseases often affect organs with high energy demands and can cause symptoms like ataxia, myopathy, seizures, and lactic acidosis. Examples of inherited mitochondrial diseases include Leber's Hereditary Optic Neuropathy and Myoclonic Epilepsy with Ragged Red Fibers.

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    Mitochondrial Diseases

    Uploaded by

    Ali Mansor
    16 views34 pages
    Mitochondrial diseases can be caused by mutations in mitochondrial DNA or nuclear DNA. mtDNA has a higher mutation rate than nuclear DNA due to lack of histones, DNA polymerase proofreading errors, and reactive oxygen species damage. Mitochondrial diseases often affect organs with high energy demands and can cause symptoms like ataxia, myopathy, seizures, and lactic acidosis. Examples of inherited mitochondrial diseases include Leber's Hereditary Optic Neuropathy and Myoclonic Epilepsy with Ragged Red Fibers.

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    Mitochondrial diseases can be caused by mutations in mitochondrial DNA or nuclear DNA. mtDNA has a higher mutation rate than nuclear DNA due to lack of histones, DNA polymerase proofreading errors, and reactive oxygen species damage. Mitochondrial diseases often affect organs with high energy demands and can cause symptoms like ataxia, myopathy, seizures, and lactic acidosis. Examples of inherited mitochondrial diseases include Leber's Hereditary Optic Neuropathy and Myoclonic Epilepsy with Ragged Red Fibers.

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    © All Rights Reserved
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    16 views34 pages

    Mitochondrial Diseases

    Uploaded by

    Ali Mansor
    Mitochondrial diseases can be caused by mutations in mitochondrial DNA or nuclear DNA. mtDNA has a higher mutation rate than nuclear DNA due to lack of histones, DNA polymerase proofreading errors, and reactive oxygen species damage. Mitochondrial diseases often affect organs with high energy demands and can cause symptoms like ataxia, myopathy, seizures, and lactic acidosis. Examples of inherited mitochondrial diseases include Leber's Hereditary Optic Neuropathy and Myoclonic Epilepsy with Ragged Red Fibers.

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    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

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