p62-Nrf2-p62 Mitophagy Regulatory Loop as a Target for Preventive Therapy of Neurodegenerative Diseases

Gureev, Artem P.; Sadovnikova, Irina S.; Starkov, Natalia N; Starkov, Anatoly A.; Popov, Vasily N.

doi:10.3390/brainsci10110847

Cited by 38 publications

(25 citation statements)

References 100 publications

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“…In the end, this might link our recent findings of a reduced antioxidative defense system in NP-C with the herein-observed defects in autophagy [22]. Likewise, p62 is thought to influence mitochondrial biogenesis, as the downstream target peroxisome proliferatoractivated receptor gamma coactivator 1-alpha (PGC-1α) of Nrf2 has been described as a master regulator of mitochondrial biogenesis [64].…”

Section: Impairement Of Autophagy In Npc1-and Npc2-deficient Cellsmentioning

confidence: 62%

Impact of Organelle Transport Deficits on Mitophagy and Autophagy in Niemann–Pick Disease Type C

Liedtke

Völkner

Hermann

et al. 2022

Cells

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Defective mitochondria are pathophysiological features of a number of neurodegenerative diseases. Here, we investigated mitochondrial dysfunction in the context of the rare lysosomal storage diseases Niemann–Pick disease type C1 and type C2 (NP-C1 and NP-C2). Mutations in either the NPC1 or NPC2 gene lead to cholesterol accumulation in late endosomes and lysosomes, resulting in impaired cholesterol homeostasis. The extent to which this may lead to mitochondrial dysfunction has been poorly studied so far. Therefore, we investigated the morphology, function, and transport of mitochondria, as well as their degradation via mitophagy, in a disease-associated human neural cell model of NP-C. By performing live cell imaging, we observed markedly reduced mitochondrial transport, although morphology and function were not appreciably altered. However, we observed a defective mitophagy induction shown by a reduced capability to elevate parkin expression and engulf mitochondria in autophagosomes after treatment with carbonyl cyanide 3-chlorophenylhydrazone (CCCP). This was accompanied by defects in autophagy induction, exhibited by a hampered p62 expression and progression, shown by increased LC3BII levels and a defective fusion of autophagosomes and lysosomes. The latter might have been additionally influenced by the observed reduced lysosomal transport. Hence, we hypothesized that a reduced recycling of mitochondria contributes to the pathophysiology of NP-C.

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Section: Impairement Of Autophagy In Npc1-and Npc2-deficient Cellsmentioning

confidence: 62%

Impact of Organelle Transport Deficits on Mitophagy and Autophagy in Niemann–Pick Disease Type C

Liedtke

Völkner

Hermann

et al. 2022

Cells

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“…3B and D ). Certain reports have shown that p62 can form a positive feedback loop with KEAP1 and NRF2 ( 9 , 25 ), and that expression levels of p62 and LC3II responds to the level of autophagy.…”

Section: Resultsmentioning

confidence: 99%

Upregulation of antioxidant and autophagy pathways via NRF2 activation protects spinal cord neurons from ozone damage

Zhang

Zhao

et al. 2021

Mol Med Rep

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Ozone therapy can relieve multiple types of pain but exhibits potential neurotoxicity, the mechanism of which is unclear. The present study aimed to identify the role of nuclear factor (erythroid-derived-2)-related 2 (NRF2) in preventing spinal cord injury caused by ozone overdose. Primary neuronal cells were extracted from newborn Wistar rats and authenticated by immunofluorescence using anti-microtubule-associated protein 2 as a cell type-specific marker. Cell viability assay with different ozone concentrations (0, 10, 20, 30 and 40 µg/ml) was used to determine the concentration that caused primary neuron injury; 30 min of 40 µg/ml ozone therapy notably decreased cell viability to 71%. In order to test the effects of ozone, the cells were divided into five treatment groups [0-, 30- and 40 µg/ml ozone, tert-butylhydroquinone (tBHQ) + 40 µg/ml ozone (T40) and tBHQ (T0)]. Cells in the T40 and T0 groups received 40 µmol/l tBHQ on the fifth day of SCN cultivation. Reverse transcription-quantitative PCR and western blotting showed that protein expression levels of heme oxygenase-1 (HO-1) and mRNA expression levels of HO-1 and NRF2 were decreased. NRF2, ubiquitin-binding protein p62 and microtubule-associated proteins 1A/1B light chain 3B expression levels were decreased following treatment with 40 µg/ml ozone. Immunofluorescence showed that NRF2 nuclear expression levels also decreased following 40 µg/ml ozone treatment. However, cells in the T40 group did not display decreased NRF2 nuclear expression levels. Normal/Apoptotic/Necrotic Cell Detection kit revealed that necrosis rate increased following treatment with 40 µg/ml ozone; however, the T40 group did not exhibit this increased necrosis. At 40 µg/ml, ozone increased spinal cord neuron (SCN) death in vitro . Moreover, treatment with 40 µg/ml ozone damaged SCNs. The p62/NRF2/antioxidant response element pathway prevented such injury. tBHQ activated this pathway, upregulated autophagy and increased local nuclear NRF2 concentration, thus enhancing the antioxidant system to protect SCNs from injury caused by high concentrations of ozone.

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“…There is crosstalk between Nrf2/ARE signalling and mitophagy crosstalk. The p62 protein is a selective mitophagy receptor for the degradation of ubiquitinated substrates [ 76 ]. There is evidence that p62 can positively regulate the Nrf2/ARE signal pathway by binding to KEAP1 (Nrf2 negative regulator).…”

Section: Discussionmentioning

confidence: 99%

Brain Protection by Methylene Blue and Its Derivative, Azur B, via Activation of the Nrf2/ARE Pathway in Cisplatin-Induced Cognitive Impairment

et al. 2022

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Cisplatin is a cytotoxic chemotherapeutic drug that leads to DNA damage and is used in the treatment of various types of tumors. However, cisplatin has several serious adverse effects, such as deterioration in cognitive ability. The aim of our work was to study neuroprotectors capable of preventing cisplatin-induced neurotoxicity. Methylene blue (MB) and AzurB (AzB) are able to neutralize the neurotoxicity caused by cisplatin by protecting nerve cells as a result of the activation of the Ntf2 signaling pathway. We have shown that cisplatin impairs learning in the Morris water maze. This is due to an increase in the amount of mtDNA damage, a decrease in the expression of most antioxidant genes, the main determinant of the induction of which is the Nrf2/ARE signaling pathway, and genes involved in mitophagy regulation in the cortex. The expression of genes involved in long-term potentiation was suppressed in the hippocampus of cisplatin-injected mice. MB in most cases prevented cisplatin-induced impairment of learning and decrease of gene expression in the cortex. AzB prevented the cisplatin-induced decrease of genes in the hippocampus. Also, cisplatin induced disbalance in the gut microbiome, decreased levels of Actinotalea and Prevotella, and increased levels of Streptococcus and Veillonella. MB and AzB also prevented cisplatin-induced changes in the bacterial composition of the gut microbiome.

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p62-Nrf2-p62 Mitophagy Regulatory Loop as a Target for Preventive Therapy of Neurodegenerative Diseases

Cited by 38 publications

References 100 publications

Impact of Organelle Transport Deficits on Mitophagy and Autophagy in Niemann–Pick Disease Type C

Impact of Organelle Transport Deficits on Mitophagy and Autophagy in Niemann–Pick Disease Type C

Upregulation of antioxidant and autophagy pathways via NRF2 activation protects spinal cord neurons from ozone damage

Brain Protection by Methylene Blue and Its Derivative, Azur B, via Activation of the Nrf2/ARE Pathway in Cisplatin-Induced Cognitive Impairment

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