Tiago Outeiro, PhD, University Medical Center
Göttingen, Göttingen, Germany, delves into the
potential mechanisms associated with Parkinson’s
disease. Starting with a focus on mitochondrial
dysfunction, a well-established factor in
parkinsonism, Prof. Outeiro highlights the
importance of understanding how interference
with mitochondrial biology can lead to cell
alterations and subsequent cell loss.
Mitochondrial
Dysfuction is at the core of Parkinson's Disease
Mitochondrial
dysfunction is a
core problem in
Parkinson's disease
(PD), affecting both
genetic and sporadic
cases, where
failing mitochondria
cause energy
deficits, increased
oxidative stress,
and cell death,
leading to the loss
of dopamine neurons.
Key issues include
impaired energy
production (electron
transport chain),
accumulation of
damaged mitochondria
(mitophagy
failure), and
interaction with
alpha-synuclein,
ultimately
contributing to
neurodegeneration
and PD symptoms.
How Mitochondria
Become Dysfunctional
in PD
Genetic Mutations:
Mutations in genes
like
PINK1 and
Parkin directly
impair mitochondrial
quality control
(mitophagy) and
function.
Alpha-Synuclein
Accumulation:
Dysfunctional
mitochondria can
trigger the buildup
of alpha-synuclein,
which then further
damages
mitochondria,
creating a vicious
cycle
.
Oxidative
Stress: Impaired
mitochondria
generate more
reactive oxygen
species (ROS),
leading to
oxidative damage
to DNA and other
cell components.
Energy Deficit:
Defective
mitochondria
produce less ATP
(energy),
starving
neurons,
especially
high-energy-demand
dopaminergic
neurons.
Impaired Quality
Control: Failure
of mitophagy
(the process to
clear out
damaged
mitochondria)
allows
dysfunctional
organelles to
persist.
Mitochondrial
Dysfunction in Genetic and Non-Genetic
Parkinson's Disease
May 7, 2025
Abstract
Mitochondrial
dysfunction is a hallmark of Parkinson's disease
(PD) pathogenesis, contributing to increased
oxidative stress and impaired
endo-lysosomal-proteasome system efficiency
underlying neuronal injury. Genetic studies have
identified 19 monogenic mutations-accounting for
~10% of PD cases-that affect mitochondrial
function and are associated with early- or
late-onset PD. Early-onset forms typically
involve genes encoding proteins essential for
mitochondrial quality control, including
mitophagy and structural maintenance, while
late-onset mutations impair mitochondrial
dynamics, bioenergetics, and trafficking.
Atypical juvenile
genetic syndromes also exhibit mitochondrial
abnormalities. In idiopathic PD, environmental
neurotoxins such as pesticides and MPTP act as
mitochondrial inhibitors, disrupting complex I
activity and increasing reactive oxygen species.
These converging pathways underscore
mitochondria as a central node in PD pathology.
This review explores the overlapping and
distinct mitochondrial mechanisms in genetic and
non-genetic PD, emphasizing their role in
neuronal vulnerability.
Targeting mitochondrial
dysfunction finally offers a promising
therapeutic avenue to slow or modify disease
progression by intervening at a key point of
neurodegenerative convergence.
Mitochondrial
Dysfunction and Parkinson's Disease:
Pathogenesis and Therapeutic Strategies
August 2023
Abstract
Parkinson's disease (PD)
is a common age-related neurodegenerative
disorder whose pathogenesis is not completely
understood. Mitochondrial dysfunction and
increased oxidative stress have been considered
as major causes and central events responsible
for the progressive degeneration of dopaminergic
(DA) neurons in PD.
Therefore, investigating
mitochondrial disorders plays a role in
understanding the pathogenesis of PD and can be
an important therapeutic target for this
disease. This study discusses the effect of
environmental, genetic and biological factors on
mitochondrial dysfunction and also focuses on
the mitochondrial molecular mechanisms
underlying neurodegeneration, and its possible
therapeutic targets in PD, including reactive
oxygen species generation, calcium overload,
inflammasome activation, apoptosis, mitophagy,
mitochondrial biogenesis, and mitochondrial
dynamics. Other potential therapeutic strategies
such as mitochondrial transfer/transplantation,
targeting microRNAs, using stem cells,
photobiomodulation, diet, and exercise were also
discussed in this review, which may provide
valuable insights into clinical aspects.
A better understanding
of the roles of mitochondria in the
pathophysiology of PD may provide a rationale
for designing novel therapeutic interventions in
our fight against PD.
International Union
of Biochemistry
https://pubmed.ncbi.nlm.nih.gov/33323315/
Mitochondrial
Dysfunction and Mitophagy in Parkinson's
Disease: From Mechanism to Therapy
April 2021
Abstract
Mitochondrial
dysfunction has been associated with
neurodegeneration in Parkinson's disease (PD)
for over 30 years. Despite this, the role of
mitochondrial dysfunction as an initiator,
propagator, or bystander remains undetermined.
The discovery of the role of the PD familial
genes PTEN-induced putative kinase 1 (PINK1) and
parkin (PRKN) in mediating mitochondrial
degradation (mitophagy) reaffirmed the
importance of this process in PD aetiology.
Recently, progress has
been made in understanding the upstream and
downstream regulators of canonical
PINK1/parkin-mediated mitophagy, alongside
noncanonical PINK1/parkin mitophagy, in response
to mitochondrial damage. Progress has also been
made in understanding the role of PD-associated
genes, such as SNCA, LRRK2, and CHCHD2, in
mitochondrial dysfunction and their overlap with
sporadic PD (sPD), opening opportunities for
therapeutically targeting mitochondria in PD.
Mitochondrial
Dysfunction in Parkinson's Disease: New
Mechanistic Insights and Therapeutic
Perspectives
April 3, 2018
Abstract
Purpose of review:
Parkinson's disease (PD) is a complex
neurodegenerative disorder, the aetiology of
which is still largely unknown. Overwhelming
evidence indicates that mitochondrial
dysfunction is a central factor in PD
pathophysiology. Here we review recent
developments around mitochondrial dysfunction in
familial and sporadic PD, with a brief overview
of emerging therapies targeting mitochondrial
dysfunction.
Recent findings:
Increasing evidence supports the critical role
for mitochondrial dysfunction in the development
of sporadic PD, while the involvement of
familial PD-related genes in the regulation of
mitochondrial biology has been expanded by the
discovery of new mitochondria-associated disease
loci and the identification of their novel
functions. Recent research has expanded
knowledge on the mechanistic details underlying
mitochondrial dysfunction in PD, with the
discovery of new therapeutic targets providing
invaluable insights into the essential role of
mitochondria in PD pathogenesis and unique
opportunities for drug development.
Parkinson's
disease (PD) is characterized by the
selective loss of dopaminergic neurons
of the substantia nigra pars compacta
(SNc) with motor and nonmotor symptoms.
Defective mitochondrial function and
increased oxidative stress (OS) have
been demonstrated as having an important
role in PD pathogenesis, although the
underlying mechanism is not clear. The
etiopathogenesis of sporadic PD is
complex with variable contributions of
environmental factors and genetic
susceptibility.
Both these
factors influence various mitochondrial
aspects, including their life cycle,
bioenergetic capacity, quality control,
dynamic changes of morphology and
connectivity (fusion, fission),
subcellular distribution (transport),
and the regulation of cell death
pathways. Mitochondrial dysfunction has
mainly been reported in various
non-dopaminergic cells and tissue
samples from human patients as well as
transgenic mouse and fruit fly models of
PD. Thus, the mitochondria represent a
highly promising target for the
development of PD biomarkers.
However, the
limited amount of dopaminergic neurons
prevented investigation of their
detailed study. For the first time, we
established human telomerase reverse
transcriptase (hTERT)-immortalized wild
type, idiopathic and Parkin deficient
mesenchymal stromal cells (MSCs)
isolated from the adipose tissues of PD
patients, which could be used as a good
cellular model to evaluate mitochondrial
dysfunction for the better understanding
of PD pathology and for the development
of early diagnostic markers and
effective therapy targets of PD. In this
review, we examine evidence for the
roles of mitochondrial dysfunction and
increased OS in the neuronal loss that
leads to PD and discuss how this
knowledge further improve the treatment
for patients with PD.
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.
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 therapie
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.
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.
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.
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.
