PHM142 UNIT 7
MITOCHONDRIAL DISEASES
PART 1 - Introduction
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The
mitochondrial
energygenerating
system
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Mitochondrial Myopathies
• Genetic defects in mitochondrial structure &
function leading to defective aerobic energy
transduction and resulting in: exercise intolerance,
lactic acidosis, stroke/seizure, headaches.
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Assays for mitochondrial dysfunction
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Nijmegen Center for Mitochondrial Disorders
The table gives the percentage of fresh muscle samples that showed an activity below
the lowest control value. Results from frozen muscle samples are not included in
this table. In total, 1,406 fresh muscle samples were examined. Of these, 39%
showed a reduced rate of ATP production from the oxidation of pyruvate and malate.
Approximately 2/3 of the samples with a reduced ATP production rate also showed a
reduced activity of one or more OXPHOS enzymes.
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PHM142 UNIT 8A
Mitochondrial dysfunction in
neurodevelopmental disorders
(e.g. autism)
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Of the 120 children with ASD studied by
Oliveira, 2005 detailed metabolic studies
including plasma lactate were performed
in 69. Elevated lactate was found in 14,
of whom 11 underwent muscle biopsy.
Five of these children were diagnosed
with definite mitochondrial disease. Thus,
4.2% of 120 children with ASD were
determined to have definite mito disease.
<> This is likely an underestimate.
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Abnormalities in Mitochondria Function in Autism
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C. Giulivi et al., 2010 JAMA 304: 2389
JAMA. 2010;304(21):2389-2396 Conclusions:
In this exploratory study, children with autism were more likely to have mitochondrial
dysfunction, mtDNA over-replication, and mtDNA deletions than typically developing
children.
Using the control values to define a reference range (set at 99% CI) for the
individual data, low NADH oxidase activity was the most common deficiency (8 of
10), followed by succinate oxidase (6/10).
The lactate-to-pyruvate ratio reflects the redox state of the cytosolic compartment,
such that a lactate-to-pyruvate ratio of 12 (as in controls) indicates a ratio of oxidized
NADH to reduced NADH of 750:1, and a lactate-to-pyruvate ratio of 6 (as in autism)
indicates a ratio of oxidized NADH to reduced NADH of 1500:1.
A more oxidized cytosolic redox state in autism could favor anaerobic glycolysis over
oxidative phosphorylation as a source of adenosine triphosphate. Although skeletal
muscle can tolerate this shift in metabolism, consequences for brain function could
be devastating due to its heavy reliance on mitochondrial oxidative phosphorylation
to generate the energy needed for cellular processes.
The rates of H2O2 production in lymphocytic mitochondria from children with
autism were higher compared with controls at both complex I and complex III.
Thus, lymphocytic mitochondria in autism not only had a lower oxidative
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phosphorylation, but also an increase in cellular oxidative stress.
PHM 142 UNIT 8B
Mitochondrial function in neurodegenerative disorders
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- The loss of autophagy-related genes results in neurodegeneration and abnormal protein
accumulation. Autophagy is a bulk lysosomal degradation pathway essential for the turnover of
long-lived, misfolded or aggregated proteins, as well as damaged or excess organelles. The
accumulation and aggregation of a-synuclein is a characteristic feature of PD. Over-expression
of a-synuclein is thought to impair autophagy, suggesting the presence of a cycle of impairment
and accumulation. Prior studies have shown that a-synuclein is degraded by chaperonemediated autophagy.
- Neurotoxins affecting humans and also used in animal models of PD: MPTP,
6-hydroxy-dopamine (6-OHDA), rotenone, and paraquat
MPTP, a selective inhibitor of PD mitochondrial complex I, directed researchers’ attention to
pathological roles of mitochondria in PD and raised the possibility that environmental toxins
affecting mitochondria might cause PD. Other mitochondrial toxins characterized as
parkinsonism-inducing reagents include 6-OHDA, rotenone, and paraquat. Studies of animal
models of PD induced with these toxins suggest that mitochondrial dysfunction and oxidative
stress are important pathogenic mechanisms. In humans, reduced complex I activity has been
reported in both post-mortem brain samples and platelets of sporadic/idiopathic PD cases.
- Lewy bodies observed in PD brain tissue are proteinaceous intracellular inclusions
containing ubiquitin and a-synuclein among many other components. The protein Parkin,
mutated in the most common cause of recessive PD, may mediate the clearance of abnormal
mitochondria through autophagy. Recent studies have revealed that genes associated with
autosomal recessive forms of PD such as PINK1 and Parkin are directly involved in
regulating mitochondrial morphology and maintenance, abnormality of which is also observed
in the more common, idiopathic forms of PD. Note however that the autosomal recessive
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PDs lack Lewy-body pathology that is characteristic of idiopathic PD.
From Fig. above
Mitochondrial fusion and fission events are required for the maintenance of a
healthy mitochondrial population (beige). Mitochondrial fusion is thought to facilitate
the interchange of internal components such as copies of the mitochondrial
genome, respiratory proteins and metabolic products. Mitochondrial fission may
play a role in the removal of dysfunctional mitochondria (dark red) with reduced
mitochondrial membrane potential (Dcm), through an autophagy-lysosomal
pathway named ‘mitophagy’.
PINK1 and Parkin are likely to be involved in this process.
PINK1 normally has a short half-life in healthy mitochondria. Upon reduction of the
Dcm, PINK1 is stabilized on the outer membrane; then accumulation of PINK1
induces the translocation of Parkin from the cytosol to the mitochondria, leading to
Parkin-dependent ubiquitination and degradation of the mitochondrial proteins, and
subsequent activation of the autophagy machinery. Ubiquitinated proteins of the
mitochondria are shown as ovals with small orange circles.
Recent studies of Parkin-deficient or PINK1-deficient mice have reported morphological and functional alterations of mitochondria in both neurons and astrocytes .
Also, a missense mutation in another gene called PARL found in PD cases
abolishes its PINK1-processing activity and the ensuing Parkin-mediated mitophagy.
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Regulation of mitophagy by PINK1 and Parkin (genes linked to PD)
Current Opinion in Neurobiology 2011, 21:935–941
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Summary a new hypothesis on mitochondrial involvement in PD
Prominent pathological features of PD include mitochondrial
dysfunction and the accumulation of protein inclusions into Lewy-bodies
in dopaminergic neurons. These disease phenotypes could arise from
impairments in the cellular quality control systems for mitochondria and
cytoplasmic proteins involving mitochondrial fission/fusion dynamics,
the ubiquitin–proteasome system, and the autophagy pathway.
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