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IUBMB Life. 2013 Mar
Mitochondria as a pharmacological
target:
Magnum overview.
Abstract
Mitochondria, responsible for energy metabolism within the
cell, act as signaling organelles. Mitochondrial dysfunction
may lead to cell death and oxidative stress and may disturb
calcium metabolism. Additionally, mitochondria play a
pivotal role in cardioprotective phenomena and a variety of
neurodegenerative disorders ranging from Parkinson's to
Alzheimer's disease.
Mitochondrial DNA mutations may lead to
impaired respiration. Hence, targeting the mitochondria with
drugs offers great potential for new therapeutic approaches.
The purpose of this overview is to present the recent state
of knowledge concerning the interactions of various
substances with mitochondria. © 2013 IUBMB Life,
65(3):273-281, 2013.
EMBO J. 2012 Jun 26
Mitochondrial dysfunction in
Parkinson's disease:
molecular mechanisms and
pathophysiological consequences.
Abstract
Neurons are critically dependent on mitochondrial integrity
based on specific morphological, biochemical, and
physiological features. They are characterized by high rates
of metabolic activity and need to respond promptly to
activity-dependent fluctuations in bioenergetic demand. The
dimensions and polarity of neurons require efficient
transport of mitochondria to hot spots of energy
consumption, such as presynaptic and postsynaptic sites.
Moreover, the postmitotic state of neurons in combination
with their exposure to intrinsic and extrinsic neuronal
stress factors call for a high fidelity of mitochondrial
quality control systems. Consequently, it is not surprising
that mitochondrial alterations can promote neuronal
dysfunction and degeneration. In particular, mitochondrial
dysfunction has long been implicated in the etiopathogenesis
of Parkinson's disease (PD), based on the observation that
mitochondrial toxins can cause parkinsonism in humans and
animal models.
Substantial progress towards understanding
the role of mitochondria in the disease process has been
made by the identification and characterization of genes
causing familial variants of PD. Studies on the function and
dysfunction of these genes revealed that various aspects of
mitochondrial biology appear to be affected in PD,
comprising mitochondrial biogenesis, bioenergetics,
dynamics, transport, and quality control.
Antioxid Redox Signal. 2012 May 1
Mitochondrial dysfunction in genetic
animal
models of Parkinson's disease.
Abstract
Mitochondria are highly dynamic, multifunctional organelles.
Aside from their major role in energy metabolism, they are
also crucial for many cellular processes including
neurotransmission, synaptic maintenance, calcium
homeostasis, cell death, and neuronal survival.
SIGNIFICANCE: Increasing evidence supports
a role for abnormal mitochondrial function in the molecular
pathophysiology of Parkinson's disease (PD). For three
decades we have known that mitochondrial toxins are capable
of producing clinical parkinsonism in humans. PD is the most
common neurodegenerative movement disorder that is
characterized by the progressive loss of substantia nigra
dopaminergic neurons leading to a deficiency of striatal
dopamine. Although the neuropathology underlying the disease
is well defined, it remains unclear why nigral dopaminergic
neurons degenerate and die.
RECENT ADVANCES: Most PD cases are
idiopathic, but there are rare familial cases. Mutations in
five genes are known to unambiguously cause monogenic
familial PD: α-synuclein, parkin, DJ-1, PTEN-induced kinase
1 (PINK1), and leucine-rich repeat kinase 2 (LRRK2). These
key molecular players are proteins of seemingly diverse
function, but with potentially important roles in
mitochondrial maintenance and function. Cell and
animal-based genetic models have provided indispensable
tools for understanding the molecular basis of PD, and have
provided additional evidence implicating mitochondrial
dysfunction as a primary pathogenic pathway leading to the
demise of dopaminergic neurons in PD.
CRITICAL ISSUES: Here, we critically
discuss the evidence for mitochondrial dysfunction in
genetic animal models of PD, and evaluate whether abnormal
mitochondrial function represents a cause or consequence of
disease pathogenesis.
FUTURE DIRECTIONS: Mitochondria may
represent a potential target for the development of
disease-modifying therapies.
Mol Neurobiol. 2011 Apr
Mitochondrial quality control and
Parkinson's disease:
a pathway unfolds.
Abstract
Recent findings from genetic studies suggest that defective
mitochondrial quality control may play an important role in
the development of Parkinson's disease (PD). Such defects
may result in the impairment of neuronal mitochondria, which
leads to both synaptic dysfunction and cell death and
results in neurodegeneration.
Here, we review
state-of-the-art knowledge of how pathways affecting
mitochondrial quality control might contribute to PD, with a
particular emphasis on the molecular mechanisms employed by
PTEN-induced putative kinase 1 (PINK1), HtrA2 and Parkin to
regulate mitochondrial quality control.
Eur J Clin Invest. 2010 Nov
Balance is the challenge--the impact
of
mitochondrial dynamics in Parkinson's disease.
Abstract
Impaired mitochondrial function has been implicated in
neurodegeneration in Parkinson's disease (PD) based on
biochemical and pathoanatomical studies in brains of PD
patients. This observation was further substantiated by the
identification of exogenic toxins, i.e. complex I inhibitors
that directly affect mitochondrial energy metabolism and
cause Parkinsonism in humans and various animal models.
Recently, insights into the underlying molecular signalling
pathways leading to alterations in mitochondrial homeostasis
were gained based on the functional characterization of
mitoprotective genes identified in rare forms of inherited
PD. Using in vitro and in vivo loss of function models of
the Parkin, PINK1, DJ-1 and Omi/HtrA2 gene, the emerging
field of mitochondrial dynamics in PD was established as
being critical for the maintenance of mitochondrial function
in neurons.
This underscored the concept that mitochondria
are highly dynamic organelles, which are tightly regulated
to continuously adapt shape to functional and anatomical
requirements during axonal transport, synaptic signalling,
organelle degradation and cellular energy supply. The
dissection of pathways involved in mitochondrial quality
control clearly established the PINK1/Parkin-pathway in the
clearance of dysfunctional mitochondria by autophagy and
hints to a complex interplay between PD-associated proteins
acting at the mitochondrial interface. The elucidation of
this mitoprotective signalling network may help to define
novel therapeutic targets for PD via molecular modelling of
mitochondria and/or pharmacological modulation of
mitochondrial dynamics.
Apoptosis. 2010 Nov
Mitochondrial dynamics, cell death
and
the pathogenesis of Parkinson's disease.
Abstract
The structure and function of the mitochondrial network is
regulated by mitochondrial biogenesis, fission, fusion,
transport and degradation. A well-maintained balance of
these processes (mitochondrial dynamics) is essential for
neuronal signaling, plasticity and transmitter release. Core
proteins of the mitochondrial dynamics machinery play
important roles in the regulation of apoptosis, and
mutations or abnormal expression of these factors are
associated with inherited and age-dependent
neurodegenerative disorders.
In Parkinson's disease (PD),
oxidative stress and mitochondrial dysfunction underlie the
development of neuropathology. The recessive
Parkinsonism-linked genes PTEN-induced kinase 1 (PINK1) and
Parkin maintain mitochondrial integrity by regulating
diverse aspects of mitochondrial function, including
membrane potential, calcium homeostasis, cristae structure,
respiratory activity, and mtDNA integrity. In addition,
Parkin is crucial for autophagy-dependent clearance of
dysfunctional mitochondria. In the absence of PINK1 or
Parkin, cells often develop fragmented mitochondria. Whereas
excessive fission may cause apoptosis, coordinated induction
of fission and autophagy is believed to facilitate the
removal of damaged mitochondria through mitophagy, and has
been observed in some types of cells.
Compensatory
mechanisms may also occur in mice lacking PINK1 that, in
contrast to cells and Drosophila, have only mild
mitochondrial dysfunction and lack dopaminergic neuron loss.
A better understanding of the relationship between the
specific changes in mitochondrial dynamics/turnover and cell
death will be instrumental to identify potentially
neuroprotective pathways steering PINK1-deficient cells
towards survival.
Such pathways may be manipulated in the
future by specific drugs to treat PD and perhaps other
neurodegenerative disorders characterized by abnormal
mitochondrial function and dynamics.
Exp Neurol. 2009 Aug;
Impaired mitochondrial dynamics and
function in the
pathogenesis of Parkinson's disease.
Abstract
Parkinson's disease (PD), the most frequent movement
disorder, is caused by the progressive loss of the dopamine
neurons within the substantia nigra pars compacta (SNc) and
the associated deficiency of the neurotransmitter dopamine
in the striatum. Most cases of PD occur sporadically with
unknown cause, but mutations in several genes have been
linked to genetic forms of PD (alpha-synuclein, Parkin,
DJ-1, PINK1, and LRRK2). These genes have provided exciting
new avenues to study PD pathogenesis and the mechanisms
underlying the selective dopaminergic neuron death in PD.
Epidemiological studies in humans, as well as molecular
studies in toxin-induced and genetic animal models of PD
show that mitochondrial dysfunction is a defect occurring
early in the pathogenesis of both sporadic and familial PD.
Mitochondrial dynamics (fission, fusion, migration) is
important for neurotransmission, synaptic maintenance and
neuronal survival. Recent studies have shown that PINK1 and Parkin play crucial roles in the regulation of mitochondrial
dynamics and function. Mutations in DJ-1 and Parkin render
animals more susceptible to oxidative stress and
mitochondrial toxins implicated in sporadic PD, lending
support to the hypothesis that some PD cases may be caused
by gene-environmental factor interactions.
A small
proportion of alpha-synuclein is imported into mitochondria,
where it accumulates in the brains of PD patients and may
impair respiratory complex I activity. Accumulation of
clonal, somatic mitochondrial DNA deletions has been
observed in the substantia nigra during aging and in PD,
suggesting that mitochondrial DNA mutations in some
instances may pre-dispose to dopamine neuron death by
impairing respiration. Besides compromising cellular energy
production, mitochondrial dysfunction is associated with the
generation of oxidative stress, and dysfunctional
mitochondria more readily mediate the induction of
apoptosis, especially in the face of cellular stress.
Collectively, the studies examined and summarized here
reveal an important causal role for mitochondrial
dysfunction in PD pathogenesis, and suggest that drugs and
genetic approaches with the ability to modulate
mitochondrial dynamics, function and biogenesis may have
important clinical applications in the future treatment of
PD.
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