Download PHM 142 UNIT 9B Mitochondrial function in neurodegenerative

PHM 142 UNIT 9B
Mitochondrial function in neurodegenerative disorders
In autism, a neurodevelopmental disorder, we discussed preliminary studies suggestive of general impairment of mitochondrial function by unknown causes.
Now we will examine mitochondrial function in neurodegenerative disorders where mitochondrial stress can cause nerve cell death. In some cases, such as Parkinson’s disease, the molecular mechanisms of mitochondria dysfunction are now being elucidated.
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A mitochondrion harbors 2 to 10 copies of mtDNA.
The mtDNA copy number is evaluated by the ratio of mtDNA to nuclear
DNA. This copy number can be modulated according to the energy needs
of the cell with changing physiological conditions, but not necessarily
coupled with mitochondrial proliferation. For instance, increases in mtDNA
copy number or mtDNA over-replication (without increases in the oxidative
phosphorylation capacity) are observed in cells in response to oxidative
stress.
The higher mtDNA copy number in ASD could represent a compensatory
mechanism to increase the number of wild-type mtDNA templates and
maintain normal levels of mitochondrial transcripts. Alternatively, these
mtDNA abnormalities could result from defective replication and/or repair of
mtDNA of primary (genetic) or secondary (oxidative damage to single base
pairs inflicted by free radicals) origins. Collectively, these results suggest
that cumulative damage and oxidative stress over time may (through
reduced capacity to generate functional mitochondria) influence the onset or
severity of autism and its comorbid symptoms.
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The number of mitochondrial proteins in mammals has been estimated to be
about 1300. To date, pathogenic defects have been found in only a fraction of
these proteins. Primary mitochondrial disease refers to disorders whose
underlying genetic cause directly impairs RC composition or function. Secondary
OXPHOS dysfunction, by contrast, has been described in a host of other genetic
or environmental disorders, including other genetic disorders (i.e., Rett
syndrome, other metabolic defects, chromosomal aneuploidies) or toxicities from
drugs (i.e., valproate, statins, pesticides).
The minimal prevalence of primary mitochondrial disease is one in 5000,
although pathogenic mutations in mitochondrial DNA (mtDNA) may occur as
frequently as one in 200 births. In the near future, developments in next
generation sequencing technologies will make it possible to include high
throughput sequence analysis in the diagnostic work-ups of mitochondrial
patients. Often, the prediction of the pathogenicity of unknown genetic variants is
not possible on the basis of sequence information alone. Usually, the level of
heteroplasmy of the mtDNA variant is checked in different tissues of the patient
and, in addition, in family members in the maternal lineage.
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Summary of a new hypothesis on mitochondrial involvement
in Parkinson’s disease (PD)
Prominent pathological features of PD include mitochondrial
dysfunction and the accumulation of protein inclusions into Lewybodies in dopaminergic neurons. Lewy bodies observed in PD
brain tissue are proteinaceous intracellular inclusions containing
ubiquitin and a-synuclein among many other components. 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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- 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 (same for rotenone), 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.
- 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
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autosomal recessive PDs lack Lewy-body pathology that is characteristic of idiopathic PD.
Mitochondrial fusion and fission events are required for the maintenance of a
healthy mitochondrial population. 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 likely plays a
role in the removal of dysfunctional mitochondria with reduced mitochondrial
membrane potential (Dcm), through an autophagy-lysosomal pathway named
‘mitophagy’.
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PINK1 and Parkin are likely to be involved in the process of mito health.
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 Parkinmediated 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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Legend for
figure in next
slide
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The ubiquitin ligase parkin mediates resistance to intracellular pathogens.
Manzanillo et al., 2013 Nature 501(7468):512-6
Abstract
Ubiquitin-mediated targeting of intracellular bacteria to the autophagy pathway is a key
innate defence mechanism against invading microbes, including the important human
pathogen Mycobacterium tuberculosis. However, the ubiquitin ligases responsible for
catalysing ubiquitin chains that surround intracellular bacteria are poorly understood. The
parkin protein is a ubiquitin ligase with a well-established role in mitophagy, and mutations
in the parkin gene (PARK2) lead to increased susceptibility to Parkinson's disease.
Surprisingly, genetic polymorphisms in the PARK2 regulatory region are also associated
with increased susceptibility to intracellular bacterial pathogens in humans, including
Mycobacterium leprae and Salmonella enterica serovar Typhi, but the function of parkin in
immunity has remained unexplored.
Here we show that parkin has a role in ubiquitin-mediated autophagy of M. tuberculosis.
Both parkin-deficient mice and flies are sensitive to various intracellular bacterial infections,
indicating parkin has a conserved role in metazoan innate defence. Moreover, our work
reveals an unexpected functional link between mitophagy and infectious disease.
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New
discovery by
Manzanillo
et al. 2013
New role of
PARKIN
(Park2) in
macrophages
and
innate
immunity
(pathway b)
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Bose and Beal, 2016 Fig. 1
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Bose and Beal, 2016 Fig. 2
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Bose and Beal, 2016 Fig. 3
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Bose and Beal, 2016 Fig. 4
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