Cell-Type-Specific Mitochondrial Quality Control in the Brain: A Plausible Mechanism of Neurodegeneration DOI Open Access
Hariprasath Ragupathy,

Manasvi Vukku,

Sandeep Kumar Barodia

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(19), P. 14421 - 14421

Published: Sept. 22, 2023

Neurodegeneration is an age-dependent progressive phenomenon with no defined cause. Aging the main risk factor for neurodegenerative diseases. During aging, activated microglia undergo phenotypic alterations that can lead to neuroinflammation, which a well-accepted event in pathogenesis of Several common mechanisms are shared by genetically or pathologically distinct diseases, such as excitotoxicity, mitochondrial deficits and oxidative stress, protein misfolding translational dysfunction, autophagy activation. Progressive loss neuronal population due increased stress leads mostly accumulation dysfunctional mitochondria. Mitochondrial dysfunction excessive neuroinflammatory responses both sufficient induce pathology neurodegeneration. Therefore, quality control key determinant health survival cells brain. Research has been primarily focused demonstrate significance health, despite important contributions non-neuronal constitute significant portion brain volume. Moreover, morphology function distinctly diverse different tissues; however, little known about their molecular diversity among cell types. dynamics types markedly decide fate overall health; therefore, it not justifiable overlook active contribution facilitating health. In this review article, we aim discuss how remarkable highly synchronized connecting property keeping neurons healthy

Language: Английский

Targeting mitophagy in Parkinson's disease DOI Creative Commons
Emily H. Clark, Aurelio Vázquez de la Torre, Tamaki Hoshikawa

et al.

Journal of Biological Chemistry, Journal Year: 2020, Volume and Issue: 296, P. 100209 - 100209

Published: Dec. 23, 2020

The genetics and pathophysiology of Parkinson's disease (PD) strongly implicate mitochondria in aetiology. Elegant studies over the last two decades have elucidated complex molecular signaling governing identification removal dysfunctional from cell, a process mitochondrial quality control known as mitophagy. Mitochondrial deficits specifically reduced mitophagy are evident both sporadic familial PD. Mendelian attributes loss-of-function mutations key regulators PINK1 Parkin to early-onset Pharmacologically enhancing accelerating damaged interest for developing disease-modifying PD therapeutic. However, despite significant understanding PINK1-Parkin-dependent -independent pathways, therapeutic potential targeting remains be fully explored. Here, we provide summary genetic evidence supporting role failure pathogenic mechanism We assess tractability pathways prospects drug discovery consider intervention points enhancement. explore numerous hit molecules beginning emerge high-content/high-throughput screening well biochemical phenotypic assays that enabled these screens. chemical biological properties reference compounds suggest many could used interrogate perturb biology validate promising targets. Finally, address considerations challenges achieving preclinical proof-of-concept, including vivo reporter methodologies models, patient stratification biomarker development forms disease.

Language: Английский

Citations

93
PGC-1s in the Spotlight with Parkinson’s Disease DOI Open Access
Elena Piccinin, Anna Maria Sardanelli,

Peter Seibel

et al.

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(7), P. 3487 - 3487

Published: March 28, 2021

Parkinson's disease is one of the most common neurodegenerative disorders worldwide, characterized by a progressive loss dopaminergic neurons mainly localized in substantia nigra pars compacta. In recent years, detailed analyses both genetic and idiopathic forms have led to better understanding molecular cellular pathways involved PD, pointing centrality mitochondrial dysfunctions pathogenic process. Failure quality control now considered hallmark disease. The peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) family acts as master regulator biogenesis. Therefore, keeping PGC-1 level proper range fundamental guarantee functional neurons. Here we review major findings that tightly bond PD PGC-1s, raising important points might lead future investigations.

Language: Английский

Citations

64
Mitochondria in Neuronal Health: From Energy Metabolism to Parkinson's Disease DOI Creative Commons

Hariharan Murali Mahadevan,

Arsalan Hashemiaghdam, Ghazaleh Ashrafi

et al.

Advanced Biology, Journal Year: 2021, Volume and Issue: 5(9)

Published: Aug. 11, 2021

Abstract Mitochondria are the main suppliers of neuronal adenosine triphosphate and play a critical role in brain energy metabolism. also serve as Ca 2+ sinks anabolic factories therefore essential for function survival. Dysregulation bioenergetics is increasingly implicated neurodegenerative disorders, particularly Parkinson's disease. This review describes mitochondria metabolism under resting conditions during synaptic transmission, presents evidence contribution mitochondrial dysfunction to

Language: Английский

Citations

62
Focusing on mitochondria in the brain: from biology to therapeutics DOI Creative Commons

Nanshan Song,

Shuyuan Mei,

Xiang-Xu Wang

et al.

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: April 17, 2024

Abstract Mitochondria have multiple functions such as supplying energy, regulating the redox status, and producing proteins encoded by an independent genome. They are closely related to physiology pathology of many organs tissues, among which brain is particularly prominent. The demands 20% resting metabolic rate holds highly active mitochondrial activities. Considerable research shows that mitochondria function, while defects induce or exacerbate in brain. In this review, we provide comprehensive advances biology involved functions, well mitochondria-dependent cellular events pathology. Furthermore, various perspectives explored better identify roles neurological diseases neurophenotypes diseases. Finally, therapies discussed. Mitochondrial-targeting therapeutics showing great potentials treatment

Language: Английский

Citations

13
Ameliorating Mitochondrial Dysfunction for the Therapy of Parkinson's Disease DOI
Qing Yin Zheng, Hanghang Liu, Yifan Gao

et al.

Small, Journal Year: 2024, Volume and Issue: 20(29)

Published: Feb. 22, 2024

Parkinson's disease (PD) is currently the second most incurable central neurodegenerative resulting from various pathogenesis. As "energy factory" of cells, mitochondria play an extremely important role in supporting neuronal signal transmission and other physiological activities. Mitochondrial dysfunction can cause accelerate occurrence progression PD. How to effectively prevent suppress mitochondrial disorders a key strategy for treatment PD root. Therefore, emerging mitochondria-targeted therapy has attracted considerable interest. Herein, relationship between PD, causes results dysfunction, major strategies ameliorating treat are systematically reviewed. The study also prospects main challenges

Language: Английский

Citations

8
Defects in Mitochondrial Biogenesis Drive Mitochondrial Alterations in PARKIN-Deficient Human Dopamine Neurons DOI Creative Commons
Manoj Kumar, Jesús A. Acevedo-Cintrón, Aanishaa Jhaldiyal

et al.

Stem Cell Reports, Journal Year: 2020, Volume and Issue: 15(3), P. 629 - 645

Published: Aug. 13, 2020

Mutations and loss of activity in PARKIN, an E3 ubiquitin ligase, play a role the pathogenesis Parkinson's disease (PD). PARKIN regulates many aspects mitochondrial quality control including autophagy (mitophagy) biogenesis. Defects mitophagy have been hypothesized to predominant dopamine (DA) neurons PD. Here, we show that although there are defects human DA lacking deficits primarily due biogenesis driven by upregulation PARIS subsequent downregulation PGC-1α. CRISPR/Cas9 knockdown completely restores function without affecting mitophagy. These results highlight importance versus PD inactivation or neurons.

Language: Английский

Citations

58
PARIS farnesylation prevents neurodegeneration in models of Parkinson’s disease DOI
Areum Jo, Yunjong Lee, Tae‐In Kam

et al.

Science Translational Medicine, Journal Year: 2021, Volume and Issue: 13(604)

Published: July 28, 2021

Farnesol enhances the amounts of farnesylated PARIS and PGC-1α, preventing dopaminergic neuronal loss in Parkinson’s disease models.

Language: Английский

Citations

51
Disruption of Mitochondrial Homeostasis: The Role of PINK1 in Parkinson’s Disease DOI Creative Commons
Maria Vizziello, Linda Borellini, Giulia Franco

et al.

Cells, Journal Year: 2021, Volume and Issue: 10(11), P. 3022 - 3022

Published: Nov. 4, 2021

The progressive reduction of the dopaminergic neurons substantia nigra is fundamental process underlying Parkinson’s disease (PD), while mechanism susceptibility this specific neuronal population largely unclear. Disturbances in mitochondrial function have been recognized as one main pathways sporadic PD since finding respiratory chain impairment animal models PD. Studies on genetic forms provided new insight role bioenergetics, homeostasis, and autophagy. PINK1 (PTEN-induced putative kinase 1) gene mutations, although rare, are second most common cause recessively inherited early-onset PD, after Parkin mutations. Our knowledge has increased dramatically last years, with discovery that a called mitophagy, which plays key maintenance health, mediated by PINK1/Parkin pathway. In vitro vivo developed, supporting synaptic transmission, particularly affecting neurons. It paramount importance to further define mitophagy homeostasis pathogenesis order delineate novel therapeutic targets.

Language: Английский

Citations

42
Novel insights into Parkin-mediated mitochondrial dysfunction and neuroinflammation in Parkinson's disease DOI Creative Commons

Sandro L. Pereira,

Dajana Großmann, Sylvie Delcambre

et al.

Current Opinion in Neurobiology, Journal Year: 2023, Volume and Issue: 80, P. 102720 - 102720

Published: April 5, 2023

Mutations in PRKN cause the second most common genetic form of Parkinson's disease (PD)-a debilitating movement disorder that is on rise due to population aging industrial world.PRKN codes for an E3 ubiquitin ligase has been well established as a key regulator mitophagy.Together with PTEN-induced kinase 1 (PINK1), Parkin controls lysosomal degradation depolarized mitochondria.But Parkin's functions go beyond mitochondrial clearance: versatile protein involved mitochondria-derived vesicle formation, cellular metabolism, calcium homeostasis, DNA maintenance, biogenesis, and apoptosis induction.Moreover, can act modulator different inflammatory pathways.In current review, we summarize latest literature concerning diverse roles maintaining healthy pool.Moreover, discuss how these recent discoveries may translate into personalized therapeutic approaches not only PRKN-PD patients but also subset idiopathic cases.

Language: Английский

Citations

21
Promising use of metformin in treating neurological disorders: biomarker-guided therapies DOI Creative Commons

Allison Loan,

Charvi Syal,

Margarita Lui

et al.

Neural Regeneration Research, Journal Year: 2023, Volume and Issue: 19(5), P. 1045 - 1055

Published: Sept. 22, 2023

Abstract Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases (Alzheimer’s disease, multiple sclerosis, Parkinson’s Huntington’s disease), cerebrovascular (stroke), neurodevelopmental (autism spectrum disorder). Although they millions individuals around world, only limited number effective treatment options available today. Since most neurological express mitochondria-related metabolic perturbations, metformin, biguanide type II antidiabetic drug, has attracted lot attention to be repurposed treat by correcting their perturbed energy metabolism. However, controversial research emerges regarding beneficial/detrimental effects metformin on these disorders. Given have complex etiology in pathophysiology influenced various risk factors such as aging, lifestyle, genetics, environment, it is important identify molecular functions can targeted These molecules then used biomarkers stratify subpopulations patients who show distinct molecular/pathological properties respond treatment, ultimately developing therapy. In this review, we will discuss perturbations impaired pathways how guide metformin-responsive for therapy

Language: Английский

Citations

17