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Mitochondrial Dysfunction in Parkinson's

10 Chronic Diseases linked to mitochondrial dysfunction

Listed below are current articles and published clinical studies documenting the
strong link between Mitochondrial Dysfunction and Parkinson's Disease.
IUBMB Life. 2013 Mar
Mitochondria as a pharmacological target:
Magnum overview.
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.
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.
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.
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.
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.
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.
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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