Multitasking guardian of mitochondrial quality: Parkin function and Parkinson’s disease

Kamienieva, I; Duszyński, Jerzy; Szczepanowska, Joanna

doi:10.1186/s40035-020-00229-8

Cited by 56 publications

(28 citation statements)

References 181 publications

(453 reference statements)

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“…Given also the differential readouts in terms of proteostatic responses and levels of tissue oxidative load upon ubiquitous or tissue-targeted park or Pink1 KD, it is likely that mitophagy displays (at least in flies) tissue-dependent regulation. However, we cannot exclude that the noted park or Pink1 genes silencing effects could be partially independent of their role in mitophagy [ 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

Nrf2 activation induces mitophagy and reverses Parkin/Pink1 knock down-mediated neuronal and muscle degeneration phenotypes

et al. 2021

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The balanced functionality of cellular proteostatic modules is central to both proteome stability and mitochondrial physiology; thus, the age-related decline of proteostasis also triggers mitochondrial dysfunction, which marks multiple degenerative disorders. Non-functional mitochondria are removed by mitophagy, including Parkin/Pink1-mediated mitophagy. A common feature of neuronal or muscle degenerative diseases, is the accumulation of damaged mitochondria due to disrupted mitophagy rates. Here, we exploit Drosophila as a model organism to investigate the functional role of Parkin/Pink1 in regulating mitophagy and proteostatic responses, as well as in suppressing degenerative phenotypes at the whole organism level. We found that Parkin or Pink1 knock down in young flies modulated proteostatic components in a tissue-dependent manner, increased cell oxidative load, and suppressed mitophagy in neuronal and muscle tissues, causing mitochondrial aggregation and neuromuscular degeneration. Concomitant to Parkin or Pink1 knock down cncC/Nrf2 overexpression, induced the proteostasis network, suppressed oxidative stress, restored mitochondrial function, and elevated mitophagy rates in flies’ tissues; it also, largely rescued Parkin or Pink1 knock down-mediated neuromuscular degenerative phenotypes. Our in vivo findings highlight the critical role of the Parkin/Pink1 pathway in mitophagy, and support the therapeutic potency of Nrf2 (a druggable pathway) activation in age-related degenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Nrf2 activation induces mitophagy and reverses Parkin/Pink1 knock down-mediated neuronal and muscle degeneration phenotypes

et al. 2021

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“…The autophagy mechanism is translocation of Parkin to defective mitochondria and recruitment of p62/SQSTM1, followed by engulfment of damaged mitochondria by autophagosomes, and degradation by lysosomes (Nguyen et al, 2016). Parkin, as a protective protein, plays many beneficial roles in preventing degenerative diseases, such as Parkinson's disease (Kamienieva et al, 2021), osteoarthritis (Ansari et al, 2018), and Alzheimer's disease (Zhao et al, 2021). However, studies regarding the relationship between Parkin and IDD are limited.…”

Section: Discussionmentioning

confidence: 99%

CRISPR/dCas9-Mediated Parkin Inhibition Impairs Mitophagy and Aggravates Apoptosis of Rat Nucleus Pulposus Cells Under Oxidative Stress

Lan

Zheng

et al. 2021

Front. Mol. Biosci.

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ObjectiveThe aim of this study is to explore the role of Parkin in intervertebral disk degeneration (IDD) and its mitophagy regulation mechanism.Study design and methodsRat nucleus pulposus (NP) cells were stimulated with hydrogen peroxide (H2O2) to a mimic pathological condition. Apoptosis and mitophagy were assessed by Western blot, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and immunofluorescence staining. The CRISPR–dCas9–KRAB system was used to silence the expression of Parkin.ResultIn this study, we found that Parkin was downregulated in rat NP cells under oxidative stress. In addition, treatment with H2O2 resulted in mitochondrial dysfunction, autophagy inhibition, and a significant increase in the rate of apoptosis of NP cells. Meanwhile, mitophagy inhibition enhanced H2O2-induced apoptosis. Furthermore, repression of Parkin significantly attenuated mitophagy and exacerbated apoptosis.ConclusionThese results suggested that Parkin may play a protective role in alleviating the apoptosis of NP cells via mitophagy, and that targeting Parkin may provide a promising therapeutic strategy for the prevention of IDD.

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“…Interestingly, independently of the ND studied, retrograde transport (towards the cell body) was often found to be increased in the disease [ 171 , 173 , 175 , 178 ]. (3) Disrupted mitophagy—mutations in mitophagy-related proteins PINK1 and PARKIN have been found in familial and sporadic forms of PD (reviewed in [ 179 , 180 ]). However, PINK1 mutations are also linked with energy deficits, as PINK1 deficiency has been shown to compromise Complex I activity [ 181 ].…”

Section: When Synaptic Energy Production Fails: Neurodegenerative Dis...mentioning

confidence: 99%

Synapses: The Brain’s Energy-Demanding Sites

Faria-Pereira

2022

IJMS

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The brain is one of the most energy-consuming organs in the mammalian body, and synaptic transmission is one of the major contributors. To meet these energetic requirements, the brain primarily uses glucose, which can be metabolized through glycolysis and/or mitochondrial oxidative phosphorylation. The relevance of these two energy production pathways in fulfilling energy at presynaptic terminals has been the subject of recent studies. In this review, we dissect the balance of glycolysis and oxidative phosphorylation to meet synaptic energy demands in both resting and stimulation conditions. Besides ATP output needs, mitochondria at synapse are also important for calcium buffering and regulation of reactive oxygen species. These two mitochondrial-associated pathways, once hampered, impact negatively on neuronal homeostasis and synaptic activity. Therefore, as mitochondria assume a critical role in synaptic homeostasis, it is becoming evident that the synaptic mitochondria population possesses a distinct functional fingerprint compared to other brain mitochondria. Ultimately, dysregulation of synaptic bioenergetics through glycolytic and mitochondrial dysfunctions is increasingly implicated in neurodegenerative disorders, as one of the first hallmarks in several of these diseases are synaptic energy deficits, followed by synapse degeneration.

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Multitasking guardian of mitochondrial quality: Parkin function and Parkinson’s disease

Cited by 56 publications

References 181 publications

Nrf2 activation induces mitophagy and reverses Parkin/Pink1 knock down-mediated neuronal and muscle degeneration phenotypes

Nrf2 activation induces mitophagy and reverses Parkin/Pink1 knock down-mediated neuronal and muscle degeneration phenotypes

CRISPR/dCas9-Mediated Parkin Inhibition Impairs Mitophagy and Aggravates Apoptosis of Rat Nucleus Pulposus Cells Under Oxidative Stress

Synapses: The Brain’s Energy-Demanding Sites

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