Regulation of Mitochondrial Dynamics in Parkinson’s Disease—Is 2-Methoxyestradiol a Missing Piece?

Mitochondria, as “power house of the cell”, are crucial players in cell pathophysiology. Beyond adenosine triphosphate (ATP) production, they take part in a generation of reactive oxygen species (ROS), regulation of cell signaling and cell death. Dysregulation of mitochondrial dynamics may lead to cancers and neurodegeneration; however, the fusion/fission cycle allows mitochondria to adapt to metabolic needs of the cell. There are multiple data suggesting that disturbed mitochondrial homeostasis can lead to Parkinson’s disease (PD) development. 2-methoxyestradiol (2-ME), metabolite of 17β-estradiol (E2) and potential anticancer agent, was demonstrated to inhibit cell growth of hippocampal HT22 cells by means of nitric oxide synthase (NOS) production and oxidative stress at both pharmacologically and also physiologically relevant concentrations. Moreover, 2-ME was suggested to inhibit mitochondrial biogenesis and to be a dynamic regulator. This review is a comprehensive discussion, from both scientific and clinical point of view, about the influence of 2-ME on mitochondria and its plausible role as a modulator of neuron survival.

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Drosophila phosphatidylinositol-4 kinase fwd promotes mitochondrial fission and can suppress Pink1/parkin phenotypes

10.1101/2020.05.13.093823 ◽

2020 ◽

Author(s):

Ana Terriente-Felix ◽

Emma L. Wilson ◽

Alexander J. Whitworth

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

High Energy ◽

Male Sterile ◽

Mitochondrial Homeostasis ◽

Locomotor Deficits ◽

Phosphatidylinositol 4

AbstractBalanced mitochondrial fission and fusion play an important role in shaping and distributing mitochondria, as well as contributing to mitochondrial homeostasis and adaptation to stress. In particular, mitochondrial fission is required to facilitate degradation of damaged or dysfunctional units via mitophagy. Two Parkinson’s disease factors, PINK1 and Parkin, are considered key mediators of damage-induced mitophagy, and promoting mitochondrial fission is sufficient to suppress the pathological phenotypes in Pink1/parkin mutant Drosophila. We sought additional factors that impinge on mitochondrial dynamics and which may also suppress Pink1/parkin phenotypes. We found that the Drosophila phosphatidylinositol 4-kinase IIIβ homologue, Four wheel drive (Fwd), promotes mitochondrial fission downstream of the pro-fission factor Drp1. Previously described only as male sterile, we identified several new phenotypes in fwd mutants, including locomotor deficits and shortened lifespan, which are accompanied by mitochondrial dysfunction. Finally, we found that fwd overexpression can suppress locomotor deficits and mitochondrial disruption in Pink1/parkin mutants, consistent with its function in promoting mitochondrial fission. Together these results shed light on the complex mechanisms of mitochondrial fission and further underscore the potential of modulating mitochondrial fission/fusion dynamics in the context of neurodegeneration.Author SummaryMitochondria are dynamic oganelles that can fuse and divide, in part to facilitate turnover of damaged components. These processes are essential to maintain a healthy mitochondrial network, and, in turn, maintain cell viability. This is critically important in high-energy, post-mitotic tissues such as neurons. We previously identified Drosophila phosphatidylinositol-4 kinase fwd as a pro-fission factor in a cell-based screen. Here we show that loss of fwd regulates mitochondrial fission in vivo, and acts genetically downstream of Drp1. We identified new phenotypes in fwd mutants, similar to loss of Pink1/parkin, two genes linked to Parkinson’s disease and key regulators of mitochondrial homeostasis. Importantly, fwd overexpression is able to substantially suppress locomotor and mitochondrial phenotypes in Pink1/parkin mutants, suggesting manipulating phophoinositides may represent a novel route to tackling Parkinson’s disease.

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Differential mitochondrial roles for α-synuclein in DRP1-dependent fission and PINK1/Parkin-mediated oxidation

Cell Death and Disease ◽

10.1038/s41419-021-04046-3 ◽

2021 ◽

Vol 12 (9) ◽

Author(s):

Thomas J. Krzystek ◽

Rupkatha Banerjee ◽

Layne Thurston ◽

JianQiao Huang ◽

Kelsey Swinter ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Mitochondrial Dynamics ◽

Dependent Manner ◽

Shape Distribution ◽

Mitochondrial Homeostasis ◽

C Terminus

AbstractMitochondria are highly dynamic organelles with strict quality control processes that maintain cellular homeostasis. Within axons, coordinated cycles of fission-fusion mediated by dynamin related GTPase protein (DRP1) and mitofusins (MFN), together with regulated motility of healthy mitochondria anterogradely and damaged/oxidized mitochondria retrogradely, control mitochondrial shape, distribution and size. Disruption of this tight regulation has been linked to aberrant oxidative stress and mitochondrial dysfunction causing mitochondrial disease and neurodegeneration. Although pharmacological induction of Parkinson’s disease (PD) in humans/animals with toxins or in mice overexpressing α-synuclein (α-syn) exhibited mitochondrial dysfunction and oxidative stress, mice lacking α-syn showed resistance to mitochondrial toxins; yet, how α-syn influences mitochondrial dynamics and turnover is unclear. Here, we isolate the mechanistic role of α-syn in mitochondrial homeostasis in vivo in a humanized Drosophila model of Parkinson’s disease (PD). We show that excess α-syn causes fragmented mitochondria, which persists with either truncation of the C-terminus (α-syn1–120) or deletion of the NAC region (α-synΔNAC). Using in vivo oxidation reporters Mito-roGFP2-ORP1/GRX1 and MitoTimer, we found that α-syn-mediated fragments were oxidized/damaged, but α-syn1–120-induced fragments were healthy, suggesting that the C-terminus is required for oxidation. α-syn-mediated oxidized fragments showed biased retrograde motility, but α-syn1–120-mediated healthy fragments did not, demonstrating that the C-terminus likely mediates the retrograde motility of oxidized mitochondria. Depletion/inhibition or excess DRP1-rescued α-syn-mediated fragmentation, oxidation, and the biased retrograde motility, indicating that DRP1-mediated fragmentation is likely upstream of oxidation and motility changes. Further, excess PINK/Parkin, two PD-associated proteins that function to coordinate mitochondrial turnover via induction of selective mitophagy, rescued α-syn-mediated membrane depolarization, oxidation and cell death in a C-terminus-dependent manner, suggesting a functional interaction between α-syn and PINK/Parkin. Taken together, our findings identify distinct roles for α-syn in mitochondrial homeostasis, highlighting a previously unknown pathogenic pathway for the initiation of PD.

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Mitochondrial dynamics and mitophagy in Parkinson's disease: A fly point of view

Neurobiology of Disease ◽

10.1016/j.nbd.2015.11.002 ◽

2016 ◽

Vol 90 ◽

pp. 58-67 ◽

Cited By ~ 31

Author(s):

Sophia Von Stockum ◽

Alice Nardin ◽

Emilie Schrepfer ◽

Elena Ziviani

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dynamics ◽

Point Of View

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PINK1: A Bridge between Mitochondria and Parkinson’s Disease

Life ◽

10.3390/life11050371 ◽

2021 ◽

Vol 11 (5) ◽

pp. 371

Author(s):

Filipa Barroso Gonçalves ◽

Vanessa Alexandra Morais

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Quality Control ◽

High Energy ◽

Common Denominator ◽

Mitochondrial Quality Control ◽

Mitochondrial Homeostasis ◽

Cellular Environment ◽

Familial Form ◽

Mitochondrial Functions

Mitochondria are known as highly dynamic organelles essential for energy production. Intriguingly, in the recent years, mitochondria have revealed the ability to maintain cell homeostasis and ultimately regulate cell fate. This regulation is achieved by evoking mitochondrial quality control pathways that are capable of sensing the overall status of the cellular environment. In a first instance, actions to maintain a robust pool of mitochondria take place; however, if unsuccessful, measures that lead to overall cell death occur. One of the central key players of these mitochondrial quality control pathways is PINK1 (PTEN-induce putative kinase), a mitochondrial targeted kinase. PINK1 is known to interact with several substrates to regulate mitochondrial functions, and not only is responsible for triggering mitochondrial clearance via mitophagy, but also participates in maintenance of mitochondrial functions and homeostasis, under healthy conditions. Moreover, PINK1 has been associated with the familial form of Parkinson’s disease (PD). Growing evidence has strongly linked mitochondrial homeostasis to the central nervous system (CNS), a system that is replenished with high energy demanding long-lasting neuronal cells. Moreover, sporadic cases of PD have also revealed mitochondrial impairments. Thus, one could speculate that mitochondrial homeostasis is the common denominator in these two forms of the disease, and PINK1 may play a central role in maintaining mitochondrial homeostasis. In this review, we will discuss the role of PINK1 in the mitochondrial physiology and scrutinize its role in the cascade of PD pathology.

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Mitophagy, a Form of Selective Autophagy, Plays an Essential Role in Mitochondrial Dynamics of Parkinson’s Disease

Cellular and Molecular Neurobiology ◽

10.1007/s10571-021-01039-w ◽

2021 ◽

Author(s):

Xiao-Le Wang ◽

Si-Tong Feng ◽

Ya-Ting Wang ◽

Yu-He Yuan ◽

Zhi-Peng Li ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Essential Role ◽

Mitochondrial Dynamics ◽

Selective Autophagy

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Stigma Experienced by Parkinson’s Disease Patients: A Descriptive Review of Qualitative Studies

Parkinson s Disease ◽

10.1155/2017/7203259 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7 ◽

Cited By ~ 15

Author(s):

Marina Maffoni ◽

Anna Giardini ◽

Antonia Pierobon ◽

Davide Ferrazzoli ◽

Giuseppe Frazzitta

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Literature Review ◽

Subjective Experience ◽

Negative Impact ◽

Social Stigma ◽

Subjective Symptom ◽

Point Of View ◽

Pubmed Database ◽

Related Quality

Parkinson’s disease (PD) is a neurodegenerative disease characterized by motor and nonmotor symptoms. Both of them imply a negative impact on Health-Related Quality of Life. A significant one is the stigma experienced by the parkinsonian patients and their caregivers. Moreover, stigma may affect everyday life and patient’s subjective and relational perception and it may lead to frustration and isolation. Aim of the present work is to qualitatively describe the stigma of PD patients stemming from literature review, in order to catch the subjective experience and the meaning of the stigma construct. Literature review was performed on PubMed database and Google Scholar (keywords: Parkinson Disease, qualitative, stigma, social problem, isolation, discrimination) and was restricted to qualitative data: 14 articles were identified to be suitable to the aim of the present overview. Results are divided into four core constructs: stigma arising from symptoms, stigma linked to relational and communication problems, social stigma arising from sharing perceptions, and caregiver’s stigma. The principal relations to these constructs are deeply analyzed and described subjectively through patients’ and caregiver’s point of view. The qualitative research may allow a better understanding of a subjective symptom such as stigma in parkinsonian patients from an intercultural and a social point of view.

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Small Extracellular Vesicles Secreted by Region-specific Astrocytes Ameliorate the Mitochondrial Function in a Cellular Model of Parkinson’s Disease

10.1101/2021.04.23.441135 ◽

2021 ◽

Author(s):

Loredana Leggio ◽

Francesca L’Episcopo ◽

Andrea Magrì ◽

María José Ulloa-Navas ◽

Greta Paternò ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Extracellular Vesicles ◽

Caspase 3 ◽

Cell Communication ◽

Mitochondrial Complex ◽

Neuron Death ◽

Atp Production ◽

Daergic Neuron ◽

Clinical Models

AbstractExtracellular vesicles (EVs) are emerging as powerful players in cell-to-cell communication both in health and diseased brain. In Parkinson’s disease (PD) – characterized by selective dopaminergic (DAergic) neuron death in ventral midbrain (VMB) and degeneration of DAergic terminals in striatum (STR) – astrocytes (AS) exert dual harmful/protective functions. When activated by chemokine CCL3, AS promote a robust DAergic neuroprotection both in cellular and pre-clinical models of PD, with mechanisms not fully elucidated. Here we used a combination of techniques to characterize AS-EVs derived from VMB and STR, and investigated their potential to exert neuroprotection. First, we show that: (i) AS of both regions secrete small EVs of ~100 nm; (ii) VMB-AS release more EVs per cell than STR-AS under basal conditions; and (iii) only VMB-AS respond to CCL3 by producing more EVs, suggesting differential AS-EV secretion rate according to PD brain region. Next, addressing AS-EV potential against oxidative stress and mitochondrial toxicity, we found that AS-EVs, especially CCL3-AS-EVs, fully counteract H2O2-induced caspase-3 activation. Furthermore, using high resolution respirometry, we demonstrated that AS-EVs rescue the neuronal mitochondrial complex I function impaired by MPP+, with VMB-AS-EVs fully restoring ATP production in MPP+-injured neurons, highlighting a regional diversity of AS-EVs with neuroprotective implications for PD.

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