Mitophagy deficiency increases NLRP3 to induce brown fat dysfunction in mice

Ko, Myoung Seok; Yun, Ji Young; Baek, In-Jeoung; Jang, Jung Eun; Hwang, Jung Jin; Lee, Seung Eun; Heo, Sun Hee; Bader, David A.; Lee, Chul‐Ho; Han, Jaeseok; Moon, Jong Seok; Lee, Jae Man; Hong, Eun Gyoung; Lee, In Kyu; Kim, Seong Who; Park, Joong Yeol; Hartig, Sean M.; Kang, Un Jung; Moore, David D.; Koh, Eun Hee; Lee, Ki Up

doi:10.1080/15548627.2020.1753002

Cited by 59 publications

(34 citation statements)

References 52 publications

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“…Previous studies showed that PINK1/PRKN‐mediated mitophagy was of physiological importance to prevent metabolic disorders in various animal models 36,37 . Global or BAT‐specific deletion of pink1 induced BAT dysfunction and obesity‐prone type in mice 8 …”

Section: Discussionmentioning

confidence: 99%

RNA‐binding protein YBX1 promotes brown adipogenesis and thermogenesis via PINK1/PRKN‐mediated mitophagy

Cao

et al. 2022

The FASEB Journal

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Promoting the thermogenic function of brown adipose tissue (BAT) is a promising strategy to combat obesity and metabolic disorders. While much is known about the transcriptional regulation of BAT activation, however, the underlying mechanism of post‐transcriptional control by RNA binding proteins remains largely unknown. Here, we found that RNA binding protein Y‐box binding protein 1 (YBX1) expression was abundant in BAT and induced by cold exposure and a β‐adrenergic agonist in mice. Loss‐of‐function experiments showed that YBX1 deficiency inhibited mouse primary brown adipocyte differentiation and thermogenic function. Further study showed that YBX1 positively regulates thermogenesis through enhancing mitophagy. Mechanistically, RNA immunoprecipitation identified that YBX1 directly targeted the transcripts of PTEN‐induced kinase 1 (Pink1) and parkin RBR E3 ubiquitin‐protein ligase (Prkn), two key regulators of mitophagy. RNA decay assay proved that loss of YBX1 decreased mRNA stability of Pink1 and Prkn, leading to reduced protein expression, thereby alleviating mitophagy and inhibiting thermogenic program. Importantly, in vivo experiments demonstrated that YBX1 overexpression in BAT promoted thermogenesis and mitophagy in mice. Collectively, our results reveal novel insight into the molecular mechanism of YBX1 in post‐transcriptional regulation of PINK1/PRKN‐mediated mitophagy and highlight the critical role of YBX1 in brown adipogenesis and thermogenesis.

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Section: Discussionmentioning

confidence: 99%

RNA‐binding protein YBX1 promotes brown adipogenesis and thermogenesis via PINK1/PRKN‐mediated mitophagy

Cao

et al. 2022

The FASEB Journal

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“…Deletion of pink1, an essential gene for mitophagy, upregulates NLRP3, brown adipose tissue dysfunction, and acquisition of an obesity-prone phenotype, although the canonical NLRP3 inflammasome is not activated. 207 In addition, autophagic flux and inflammasome activation are linked to the promotion of NLRP3 inflammasomemediated pathological inflammation induced by 1deoxysphingolipids (deoxySLs), atypical sphingolipids that are elevated in patients with hereditary sensory and autonomic neuropathy (HSAN1) or T2DM. 208 Rapidly accumulating evidence regarding the cross talk between autophagy components and the inflammasome that regulates immune responses has provided new insights that are likely to lead to the development of novel therapeutic approaches for treating NLRP3-related diseases.…”

Section: Dual Regulatory Mechanisms Controlling the Nlrp3 Inflammasomementioning

confidence: 99%

An update on the regulatory mechanisms of NLRP3 inflammasome activation

et al. 2021

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The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein complex involved in the release of mature interleukin-1β and triggering of pyroptosis, which is of paramount importance in a variety of physiological and pathological conditions. Over the past decade, considerable advances have been made in elucidating the molecular mechanisms underlying the priming/licensing (Signal 1) and assembly (Signal 2) involved in NLRP3 inflammasome activation. Recently, a number of studies have indicated that the priming/licensing step is regulated by complicated mechanisms at both the transcriptional and posttranslational levels. In this review, we discuss the current understanding of the mechanistic details of NLRP3 inflammasome activation with a particular emphasis on protein-protein interactions, posttranslational modifications, and spatiotemporal regulation of the NLRP3 inflammasome machinery. We also present a detailed summary of multiple positive and/or negative regulatory pathways providing upstream signals that culminate in NLRP3 inflammasome complex assembly. A better understanding of the molecular mechanisms underlying NLRP3 inflammasome activation will provide opportunities for the development of methods for the prevention and treatment of NLRP3 inflammasome-related diseases.

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“…However, excess mitophagy causes a reduction in mitochondrial number and bioenergetics failure, while lysosome enlargement and lysosomal membrane permeabilization (LMP) lead to leakage of digestive enzymes to the cytosol [ 20 , 29 ]. Conversely, a slow mitophagy leads to the accumulation of damaged mitochondria releasing mtROS and oxidized mtDNA, which activate NOD-like LRR and pyrin domain-containing protein 3 (NLRP3) inflammasome and caspase-1 dependent interleukin IL-1β/IL-18 processing and pyroptosis via gasdermin-D mediated plasma membrane pore formation [ 14 , 30 ]. Thus, maintaining an optimal mitophagic flux, mitogenesis, and lysosome biosynthesis is needed.…”

Section: Introductionmentioning

confidence: 99%

Potential Combination Drug Therapy to Prevent Redox Stress and Mitophagy Dysregulation in Retinal Müller Cells under High Glucose Conditions: Implications for Diabetic Retinopathy

Singh

Devi

2021

Diseases

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Chronic hyperglycemia-induced thioredoxin-interacting protein (TXNIP) expression, associated oxidative/nitrosative stress (ROS/RNS), and mitochondrial dysfunction play critical roles in the etiology of diabetic retinopathy (DR). However, there is no effective drug treatment to prevent or slow down the progression of DR. The purpose of this study is to examine if a combination drug treatment targeting TXNIP and the mitochondria-lysosome pathway prevents high glucose-induced mitochondrial stress and mitophagic flux in retinal Müller glial cells in culture, relevant to DR. We show that diabetes induces TXNIP expression, redox stress, and Müller glia activation (gliosis) in rat retinas when compared to non-diabetic rat retinas. Furthermore, high glucose (HG, 25 mM versus low glucose, LG 5.5 mM) also induces TXNIP expression and mitochondrial stress in a rat retinal Müller cell line, rMC1, in in vitro cultures. Additionally, we develop a mitochondria-targeted mCherry and EGFP probe tagged with two tandem COX8a mitochondrial target sequences (adenovirus-CMV-2×mt8a-CG) to examine mitophagic flux in rMC1. A triple drug combination treatment was applied using TXNIP-IN1 (which inhibits TXNIP interaction with thioredoxin), Mito-Tempo (mitochondrial anti-oxidant), and ML-SA1 (lysosome targeted activator of transient calcium channel MCOLN1/TRPML1 and of transcription factor TFEB) to study the mitochondrial–lysosomal axis dysregulation. We found that HG induces TXNIP expression, redox stress, and mitophagic flux in rMC1 versus LG. Treatment with the triple drug combination prevents mitophagic flux and restores transcription factor TFEB and PGC1α nuclear localization under HG, which is critical for lysosome biosynthesis and mitogenesis, respectively. Our results demonstrate that 2×mt8a-CG is a suitable probe for monitoring mitophagic flux, both in live and fixed cells in in vitro experiments, which may also be applicable to in vivo animal studies, and that the triple drug combination treatment has the potential for preventing retinal injury and disease progression in diabetes.

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Mitophagy deficiency increases NLRP3 to induce brown fat dysfunction in mice

Cited by 59 publications

References 52 publications

RNA‐binding protein YBX1 promotes brown adipogenesis and thermogenesis via PINK1/PRKN‐mediated mitophagy

RNA‐binding protein YBX1 promotes brown adipogenesis and thermogenesis via PINK1/PRKN‐mediated mitophagy

An update on the regulatory mechanisms of NLRP3 inflammasome activation

Potential Combination Drug Therapy to Prevent Redox Stress and Mitophagy Dysregulation in Retinal Müller Cells under High Glucose Conditions: Implications for Diabetic Retinopathy

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