BNIP3L/NIX degradation leads to mitophagy deficiency in ischemic brains

Wu, Xiaoli; Zheng, Yanrong; Liu, Mengru; Li, Yue; Ma, Shijia; Tang, Weidong; Yan, Wenping; Cao, Ming; Zheng, Wanqing; Jiang, Lei; Wu, Jiaying; Han, Feng; Qin, Zheng‐Hong; Fang, Liang; Hu, Weiwei; Chen, Zhong; Zhang, Xiangnan

doi:10.1080/15548627.2020.1802089

Cited by 120 publications

(71 citation statements)

References 66 publications

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“…Notably, antioxidant NAC and MitoQ-mediated suppression of HIF-1α levels also diminished the expression of BNIP3 and NIX. Interestingly, BNIP3 and NIX deficiency have been linked to defective mitophagy leading to excessive ROS production [ 60 , 61 ], suggesting that ROS generating defective mitochondria requires BNIP3/NIX for their mitophagy. We found that indeed BNIP3 and NIX play crucial roles in CoCl 2 -induced mitophagy but the extent of mitochondrial ubiquitination in BNIP3-NIX DKO increased probably due to a block in mitophagy and possibly due to compromised autophagy in general [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Ubiquitination and receptor-mediated mitophagy converge to eliminate oxidation-damaged mitochondria during hypoxia

et al. 2021

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The contribution of the Ubiquitin-Proteasome System (UPS) to mitophagy has been largely attributed to the E3 ubiquitin ligase Parkin. Here we show that in response to the oxidative stress associated with hypoxia or the hypoxia mimic CoCl 2 , the damaged and fragmented mitochondria are removed by Parkin-independent mitophagy. Mitochondria isolated from hypoxia or CoCl 2 -treated cells exhibited extensive ubiquitination, predominantly Lysine 48-linked and involves the degradation of key mitochondrial proteins such as the mitofusins MFN1/2, or the import channel component TOM20. Reflecting the critical role of mitochondrial protein degradation, proteasome inhibition blocked CoCl 2 -induced mitophagy. The five conserved ubiquitin-binding autophagy receptors (p62, NDP52, Optineurin, NBR1, TAX1BP1) were dispensable for the ensuing mitophagy, suggesting that the mitophagy step itself was independent of ubiquitination. Instead, the expression of two ubiquitin-independent mitophagy receptor proteins BNIP3 and NIX was induced by hypoxia or CoCl 2 -treatment followed by their recruitment to the oxidation-damaged mitochondria. By employing BNIP3/NIX double knockout and DRP1-null cell lines, we confirmed that mitochondrial clearance relies on DRP1-dependent mitochondrial fragmentation and BNIP3/NIX-mediated mitophagy. General antioxidants such as N -Acetyl Cysteine (NAC) or the mitochondria-specific Mitoquinone prevented HIF-1α stabilization, ameliorated hypoxia-related mitochondrial oxidative stress, and suppressed mitophagy. We conclude that the UPS and receptor-mediated autophagy converge to eliminate oxidation-damaged mitochondria.

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Section: Discussionmentioning

confidence: 99%

Ubiquitination and receptor-mediated mitophagy converge to eliminate oxidation-damaged mitochondria during hypoxia

et al. 2021

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“…Then, NIX was obtained ( Figure 4(a) ). NIX was reported to play a protective role by promoting mitochondrial autophagy in neurodegenerative diseases [ 23 ]. The target binding relationship between miR-30b and NIX was verified by dual-luciferase assay in 293T cells ( Figure 4(b) ).…”

Section: Resultsmentioning

confidence: 99%

Baicalein Mediates Mitochondrial Autophagy via miR-30b and the NIX/BNIP3 Signaling Pathway in Parkinson’s Disease

Chen

Peng

Gong

et al. 2021

Biochemistry Research International

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Parkinson’s disease (PD) is regarded as a severe neurodegenerative disorder. Baicalein is involved in the treatment of PD. This study explored the mechanism of baicalein in PD. The PD rat model was established using 6-hydroxydopamine. The neurologic score, dopamine (DA) content, apoptotic cells, and neuronal damage were evaluated after rats were treated with baicalein. Autophagy in PD rats was inhibited using 3-methyladenine (3-MA). The mitochondrial membrane potential (MMP) and autophagy-related proteins (LC3, P62) were detected. Next, agomiR-30b was transfected into PD rats. The targeting relation between miR-30b and NIX was predicted and verified. Then, sh-NIX was transfected into PD rats, and the effects of miR-30b and NIX on MMP, LC3, and P62 were assessed. When miR-30b was overexpressed using agomiR-30b, the NIX and BNIP3 levels were detected. Baicalein increased the neurological score and restored DA content, neurons, MMP, and mitochondrial autophagy protein levels. Baicalein inhibited miR-30b expression and miR-30b targeted NIX. miR-30b upregulation or NIX silencing reversed the effect of baicalein on MMP and mitochondrial autophagy. Baicalein upregulated NIX and BNIP3 expressions, while miR-30b overexpression inhibited NIX and BNIP3 expressions. In summary, baicalein mediated mitochondrial autophagy and restored neuronal activity by downregulating miR-30b and activating the NIX/BNIP3 pathway, thus protecting against PD.

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“…Mitochondria function as the primary source of intracellular ATP to supply energy for the neurons under physiological conditions; however, they are very susceptible to pathological insults (e.g., hypoxia and toxins) and contribute to the generation of free radicals and cell apoptosis under pathological conditions. Previous studies by us and the others demonstrated that the structure and function of mitochondria were impaired during cerebral I/R injury, accompanied by the increased levels of ROS and neuronal apoptosis [28,52]. Excessive free radicals also induce peroxidation to biomacromolecules, including lipid, protein, and nucleic acid and aggravate cellular damage and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin‐Specific Protease 29 Exacerbates Cerebral Ischemia‐Reperfusion Injury in Mice

Hou

Shen

Wan

et al. 2021

Oxidative Medicine and Cellular Longevity

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Oxidative stress and apoptosis contribute to the progression of cerebral ischemia/reperfusion (I/R) injury. Ubiquitin-specific protease 29 (USP29) is abundantly expressed in the brain and plays critical roles in regulating oxidative stress and cell apoptosis. The purpose of the present study is to investigate the role and underlying mechanisms of USP29 in cerebral I/R injury. Neuron-specific USP29 knockout mice were generated and subjected to cerebral I/R surgery. For USP29 overexpression, mice were stereotactically injected with the adenoassociated virus serotype 9 vectors carrying USP29 for 4 weeks before cerebral I/R. And primary cortical neurons were isolated and exposed to oxygen glucose deprivation/reperfusion (OGD/R) stimulation to imitate cerebral I/R injury in vitro. USP29 expression was elevated in the brain and primary cortical neurons upon I/R injury. Neuron-specific USP29 knockout significantly diminished, whereas USP29 overexpression aggravated cerebral I/R-induced oxidative stress, apoptosis, and neurological dysfunction in mice. In addition, OGD/R-induced oxidative stress and neuronal apoptosis were also attenuated by USP29 silence but exacerbated by USP29 overexpression in vitro. Mechanistically, neuronal USP29 enhanced p53/miR-34a-mediated silent information regulator 1 downregulation and then promoted the acetylation and suppression of brain and muscle ARNT-like protein, thereby aggravating oxidative stress and apoptosis upon cerebral I/R injury. Our findings for the first time identify that USP29 upregulation during cerebral I/R may contribute to oxidative stress, neuronal apoptosis, and the progression of cerebral I/R injury and that inhibition of USP29 may help to develop novel therapeutic strategies to treat cerebral I/R injury.

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BNIP3L/NIX degradation leads to mitophagy deficiency in ischemic brains

Cited by 120 publications

References 66 publications

Ubiquitination and receptor-mediated mitophagy converge to eliminate oxidation-damaged mitochondria during hypoxia

Ubiquitination and receptor-mediated mitophagy converge to eliminate oxidation-damaged mitochondria during hypoxia

Baicalein Mediates Mitochondrial Autophagy via miR-30b and the NIX/BNIP3 Signaling Pathway in Parkinson’s Disease

Ubiquitin‐Specific Protease 29 Exacerbates Cerebral Ischemia‐Reperfusion Injury in Mice

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