Mitochondrial disease - WordPress.com...Mitochondrial disease: manifestation and inheritance • Clinical expression of a genetic disorder comprises both unique gene inheritance (mitochondria)

10/6/2009

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What are mitochondria?

What are mitochondria?

• An intracellular organelle.

• There are 100 to 1000s of mitochondria/cell.

• Most mitochondria come from the mother.

• Mitochondria have their own DNA• Mitochondria have their own DNA.

• Found in all cell types, except the RBC.

• Major functions of mitochondria:

– Makes energy in the form of ATP.

– Programmed cell death (apoptosis).

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Bioenergetics

(Saneto, Russel, Univ.Washington)

History: Disease


History: Disease

• 1962: Luft et al. (J Clin Invest 1962;41:1776)

– Described a woman having a hyper‐metabolic state, structurally abnormal mitochondria, and abnormalities of oxidative phosphorylation.


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• 1963: Nass and Nass (J Cell Biol 1963;19:593)

– Described mitochondrial DNA.

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History: Disease

• 1963: Engle and Cunningham (Neurology 1963;13:919) – Described ragged red fibers.

• 1988: First description of mitochondria DNA mutations, insertion‐deletions and base substitutions causing disease


substitutions, causing disease.– Kearns‐Sayre/Chronic progressive external ophthalmoplegia (Holt et al., Nature 1988;331:717).

– Leber’s Heredity Optic Neuritis (Wallace et al., Science 1988;242:1427).

Taylor and Turnbull, 2005 Taylor and Turnbull, 2005

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This exceptionally wide clinical spectrum can be attributed to the range of mitochondrial function:

• oxidative ATP production

• synthesis of iron–sulphur clusters, haem, amino acids, steroid hormones and neurotransmitterssteroid hormones and neurotransmitters,

• regulation of cytoplasmic calcium levels and key events in apoptosis.

However, most of the known mitochondrial disorders

are caused primarily by

a dysfunctional respiratory chain

Protein subunits of the five respiratory chain complexes encoded by nuclear and mitochondrial genes.

• Respiratory complexes (I–V) embedded in the lipid bilayer of the inner mitochondrial membrane.

• Arrows (green) show the pathway of electrons from the various electron donors. Broken arrows (blue) show the sites ofarrows (blue) show the sites of proton pumping from the matrix side to the cytosolic side by complexes I, III, and IV. The red arrow shows the flow of protons through complex V from the cytosolic side to the matrix coupled to the synthesis of ATP.

• Indicated above each complex are the number of protein subunits encoded by nuclear (nDNA) and mitochondrial (mtDNA) genomes.

Taylor and Turnbull, 2005


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Mitochondrial disease: manifestation and inheritance

• Clinical expression of a genetic disorder comprises both unique gene inheritance (mitochondria) and standard autosomal and x‐linked processes.


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• Clinical expression of the disease represents the integration of both unique and common genetic processes, and the unusual cell biology of mitochondria.

In need of answers:mtDNA diseases

Cell Biology of Mitochondria

• Multiple mitochondrion per cell

• Complementation

• Heteroplasmy


• Threshold level

• Stochastic redistribution

• End‐organ susceptibility


• Multiple mitochondrion per cell– Varies between 100s to 1000s, depending on energy demand.

• Complementation– As with mtDNA, normal mitochondria can complement or


“normalize” abnormal mitochondria function within a cell. As with mtDNA, there is a threshold effect. Mitochondria with ETC dysfunction can also complement one another with mitochondria proliferation to compensate for mildly compromised ATP production.

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• Homoplasmy– Homoplasmy is a condition of complete “wild type” or normal mitochondra per cell. It can also be completely abnormal mitochondria per cell (at th tDNA d ll l l)


the mtDNA and organelle level).

• Heteroplasmy– Presence of both normal and abnormal mitochondria within a cell or organ.


• Threshold– The energetic minimum at which a cell or organ or organism needs to function.

• Changes during development


• Changes during stress or illness (i.e. brown outages during peak electrical use)

• Varies between organs (e.g. brain activity versus mature epidermal cell)

– High energy demand tissues/states are more sensitive to heteroplasmy.


• Stochastic Redistribution

– At cell division, redistribution of mitochondria is random.

– This changes the degree of heteroplasmy from cell


generation to cell generation.

– Obviously, those cells that do not undergo cell division do not change their heteroplasmy by redistribution.

• Brain and muscle.

– Collect abnormal mitochondria.


• Organ Susceptibility– Dividing cells tend to select against abnormal mitochondria.

– Non‐dividing cells tend to collect abnormal


mitochondria.

– High energy demanding organs are more sensitive to heteroplasmy

– Conditions of growth, stress, and illness lower threshold for bioenergetic disease.

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Epidemiology


Are these diseases common?

Mitochondrial dysfunction

• is a major cause of inherited metabolic diseases, • has an important role in age‐related pathologies such as – cancer, type II diabetes– type II diabetes

– neurodegeneration, – and possibly even in normal ageing

• mitochondrial DNA (mtDNA ) mutations have an estimated prevalence of 1:200 and carrier frequencies of more than 1:100 for nuclear‐encoded gene mutations in Western populations

Diagnosis of Mitochondrial Cytopathies

Lab Results Clinical Exam and History


CNS Imaging Biopsy Data

Mitochondrial Cytopathy

Important points

• Diagnosis is not based on a single test, but using multiple tests.– History, Physical exam, Lab, Neuroimaging, & Muscle biposy.

• Note that there is multi‐systemic illness that is not unified by a single syndrome or disease


unified by a single syndrome or disease.– Variation in phenotypic presentation.

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Important Points

• Mitochondrial Cytopathies– Suspect when > 2 unrelated organ systems are involved.

– Suspect when inheritance seems maternal.


– Suspect when the neurological exam seems paradoxical.

– Suspect when the usual presentation of a syndrome is not “usual” and history is suspect for a bioenergetic disorder.

Important Points

• Diagnosis of a Mitochondrial Cytopathy

– History (history, history, history)

– Good neurological examination

Multiple labs (best drawn when ill)


– Multiple labs (best drawn when ill)

– Subtle findings, even within the “normal range”

– No standard, therefore, clinical acumen of extreme importance

Mitochondrial Inheritance Patterns


Asymptomatic sibling with mtDNA mutation



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Mechanism of the disease

Manipulation of mitochondrial DNA or proteins involvedin its maintenance in mice

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Mito in ROS metabolism

Mito in neurodegenerative disease

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Therapeutic intervention

Different approaches address different stages of the pathological process.

• therapy to increase the respiratory activity and the

• The first two are thought to work as a chronic, preventive therapy before the patient reports any seriou disease manifestationss.

• At the onset clinical manifestation, the therapeuticalapproach would be an anti‐

( ldrespiratory activity and the ATP synthesis,

• therapy to titrate the excess oxidative stress,

• therapy to limit or inhibit the apoptotic cascade.

apoptotic strategy (Waldmeier, 2003).

• The details with which the pathological events occur in the transition from the subclinical changes observable at the examination to the frank onset of the disease are essential to define the window of opportunity for a therapeutical intervention.


Poulton et al

Concluding remarks

• Mitochondrial cytopathies are common diseases.

• Phenotypic expression of mitochondrial diseases are varied and high index of suspicion is necessary for diagnosis.

Wh h i l d i h


• When greater than two systems are involved without a logical explanation, think of mitochondrial disease.

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Mitochondrial disease - WordPress.com...Mitochondrial disease: manifestation and inheritance • Clinical expression of a genetic disorder comprises both unique gene inheritance (mitochondria)