Dietary Antioxidants and the Mitochondrial Quality Control: Their Potential Roles in Parkinson’s Disease Treatment

Advances in medicine and dietary standards over recent decades have remarkably increased human life expectancy. Unfortunately, the chance of developing age-related diseases, including neurodegenerative diseases (NDDs), increases with increased life expectancy. High metabolic demands of neurons are met by mitochondria, damage of which is thought to contribute to the development of many NDDs including Parkinson’s disease (PD). Mitochondrial damage is closely associated with the abnormal production of reactive oxygen species (ROS), which are widely known to be toxic in various cellular environments, including NDD contexts. Thus, ways to prevent or slow mitochondrial dysfunction are needed for the treatment of these NDDs. In this review, we first detail how ROS are associated with mitochondrial dysfunction and review the cellular mechanisms, such as the mitochondrial quality control (MQC) system, by which neurons defend against both abnormal production of ROS and the subsequent accumulation of damaged mitochondria. We next highlight previous studies that link mitochondrial dysfunction with PD and how dietary antioxidants might provide reinforcement of the MQC system. Finally, we discuss how aging plays a role in mitochondrial dysfunction and PD before considering how healthy aging through proper diet and exercise may be salutary.

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Current Progress of Mitochondrial Quality Control Pathways Underlying the Pathogenesis of Parkinson’s Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/4578462 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 6

Author(s):

Xue Jiang ◽

Tao Jin ◽

Haining Zhang ◽

Jing Miao ◽

Xiuzhen Zhao ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Quality Control ◽

Mitochondrial Dysfunction ◽

Neurodegenerative Disorder ◽

Mitochondrial Dynamics ◽

Alpha Synuclein ◽

Substantia Nigra Pars Compacta ◽

Toxic Metabolite ◽

Mitochondrial Quality Control

Parkinson’s disease (PD), clinically characterized by motor and nonmotor symptoms, is a common progressive and multisystem neurodegenerative disorder, which is caused by both genetic and environmental risk factors. The main pathological features of PD are the loss of dopaminergic (DA) neurons and the accumulation of alpha-synuclein (α-syn) in the residual DA neurons in the substantia nigra pars compacta (SNpc). In recent years, substantial progress has been made in discovering the genetic factors of PD. In particular, a total of 19 PD-causing genes have been unraveled, among which some members have been regarded to be related to mitochondrial dysfunction. Mitochondria are key regulators of cellular metabolic activity and are critical for many important cellular processes including energy metabolism and even cell death. Their normal function is basically maintained by the mitochondrial quality control (MQC) mechanism. Accordingly, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a kind of neurotoxin, exerts its neurotoxic effects at least partially by producing its toxic metabolite, namely, 1-methyl-4-phenylpyridine (MPP+), which in turn causes mitochondrial dysfunction by inhibiting complex I and mimicking the key features of PD pathogenesis. This review focused on three main aspects of the MQC signaling pathways, that is, mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial autophagy; hence, it demonstrates in detail how genetic and environmental factors result in PD pathogenesis by interfering with MQC pathways, thereby hopefully contributing to the discovery of novel potential therapeutic targets for PD.

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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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Amelioration of Mitochondrial Quality Control and Proteostasis by Natural Compounds in Parkinson’s Disease Models

International Journal of Molecular Sciences ◽

10.3390/ijms20205208 ◽

2019 ◽

Vol 20 (20) ◽

pp. 5208 ◽

Cited By ~ 7

Author(s):

Bongki Cho ◽

Taeyun Kim ◽

Yu-Jin Huh ◽

Jaemin Lee ◽

Yun-Il Lee

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Neurodegenerative Disorder ◽

Ubiquitin Proteasome System ◽

Natural Compounds ◽

Cellular Damage ◽

Pathophysiological Mechanism ◽

Neuroprotective Effects ◽

Age Related

Parkinson’s disease (PD) is a well-known age-related neurodegenerative disorder associated with longer lifespans and rapidly aging populations. The pathophysiological mechanism is a complex progress involving cellular damage such as mitochondrial dysfunction and protein homeostasis. Age-mediated degenerative neurological disorders can reduce the quality of life and also impose economic burdens. Currently, the common treatment is replacement with levodopa to address low dopamine levels; however, this does not halt the progression of PD and is associated with adverse effects, including dyskinesis. In addition, elderly patients can react negatively to treatment with synthetic neuroprotection agents. Recently, natural compounds such as phytochemicals with fewer side effects have been reported as candidate treatments of age-related neurodegenerative diseases. This review focuses on mitochondrial dysfunction, oxidative stress, hormesis, proteostasis, the ubiquitin‒proteasome system, and autophagy (mitophagy) to explain the neuroprotective effects of using natural products as a therapeutic strategy. We also summarize the efforts to use natural extracts to develop novel pharmacological candidates for treatment of age-related PD.

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PINK1 and Parkin mitochondrial quality control: a source of regional vulnerability in Parkinson’s disease

Molecular Neurodegeneration ◽

10.1186/s13024-020-00367-7 ◽

2020 ◽

Vol 15 (1) ◽

Cited By ~ 17

Author(s):

Preston Ge ◽

Valina L. Dawson ◽

Ted M. Dawson

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Quality Control ◽

Mitochondrial Quality Control ◽

Regional Vulnerability

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PINK1, Parkin, and Mitochondrial Quality Control: What can we Learn about Parkinson’s Disease Pathobiology?

Journal of Parkinson s Disease ◽

10.3233/jpd-160989 ◽

2017 ◽

Vol 7 (1) ◽

pp. 13-29 ◽

Cited By ~ 92

Author(s):

Dominika Truban ◽

Xu Hou ◽

Thomas R. Caulfield ◽

Fabienne C. Fiesel ◽

Wolfdieter Springer

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Quality Control ◽

Mitochondrial Quality Control

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Targeting the Mitochondria-Proteostasis Axis to Delay Aging

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.656201 ◽

2021 ◽

Vol 9 ◽

Cited By ~ 1

Author(s):

Andreas Zimmermann ◽

Corina Madreiter-Sokolowski ◽

Sarah Stryeck ◽

Mahmoud Abdellatif

Keyword(s):

Quality Control ◽

Therapeutic Potential ◽

Human Life ◽

Molecular Targets ◽

Protein Homeostasis ◽

Novel Therapies ◽

Pharmacological Interventions ◽

Mitochondrial Quality Control ◽

Age Related ◽

Organ Systems

Human life expectancy continues to grow globally, and so does the prevalence of age-related chronic diseases, causing a huge medical and economic burden on society. Effective therapeutic options for these disorders are scarce, and even if available, are typically limited to a single comorbidity in a multifaceted dysfunction that inevitably affects all organ systems. Thus, novel therapies that target fundamental processes of aging itself are desperately needed. In this article, we summarize current strategies that successfully delay aging and related diseases by targeting mitochondria and protein homeostasis. In particular, we focus on autophagy, as a fundamental proteostatic process that is intimately linked to mitochondrial quality control. We present genetic and pharmacological interventions that effectively extend health- and life-span by acting on specific mitochondrial and pro-autophagic molecular targets. In the end, we delve into the crosstalk between autophagy and mitochondria, in what we refer to as the mitochondria-proteostasis axis, and explore the prospect of targeting this crosstalk to harness maximal therapeutic potential of anti-aging interventions.

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Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Cells ◽

10.3390/cells9030598 ◽

2020 ◽

Vol 9 (3) ◽

pp. 598 ◽

Cited By ~ 9

Author(s):

Anna Picca ◽

Riccardo Calvani ◽

Hélio José Coelho-Junior ◽

Francesco Landi ◽

Roberto Bernabei ◽

...

Keyword(s):

Quality Control ◽

Mitochondrial Dysfunction ◽

Mitochondrial Dynamics ◽

Mitochondrial Quality Control ◽

Membrane Contact Sites ◽

Contact Sites ◽

Age Related ◽

Bidirectional Communication ◽

Membrane Contact ◽

Organelle Membrane

Mitochondrial dysfunction and failing mitochondrial quality control (MQC) are major determinants of aging. Far from being standalone organelles, mitochondria are intricately related with cellular other compartments, including lysosomes. The intimate relationship between mitochondria and lysosomes is reflected by the fact that lysosomal degradation of dysfunctional mitochondria is the final step of mitophagy. Inter-organelle membrane contact sites also allow bidirectional communication between mitochondria and lysosomes as part of nondegradative pathways. This interaction establishes a functional unit that regulates metabolic signaling, mitochondrial dynamics, and, hence, MQC. Contacts of mitochondria with the endoplasmic reticulum (ER) have also been described. ER-mitochondrial interactions are relevant to Ca2+ homeostasis, transfer of phospholipid precursors to mitochondria, and integration of apoptotic signaling. Many proteins involved in mitochondrial contact sites with other organelles also participate to degradative MQC pathways. Hence, a comprehensive assessment of mitochondrial dysfunction during aging requires a thorough evaluation of degradative and nondegradative inter-organelle pathways. Here, we present a geroscience overview on (1) degradative MQC pathways, (2) nondegradative processes involving inter-organelle tethering, (3) age-related changes in inter-organelle degradative and nondegradative pathways, and (4) relevance of MQC failure to inflammaging and age-related conditions, with a focus on Parkinson’s disease as a prototypical geroscience condition.

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