Targeting MCL1 to induce mitophagy is a potential therapeutic strategy for Alzheimer disease

Cen, Xufeng; Xu, Xiaoyan; Xia, Hongguang

doi:10.1080/15548627.2020.1860542

Cited by 20 publications

(15 citation statements)

References 1 publication

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“…This paradigm-shifting finding indicates a unique mechanism suggesting that MCL1 has an autophagy receptor function. Mechanistically, UMI-77 presumably exposes the LIR motif in MCL1 protein to LC3, thus facilitating the interaction of LC3 and MCL1 [128]. In agreement with this model, administration of UMI-77 alleviates AD phenotypes, such as by improving cognitive impairment, decreasing Aβ deposition in the brain, and diminishing inflammatory-cytokine levels, in an APP/PS1-transgenic mouse model [54].…”

Section: Targeting Of Mcl1 With Bh3 Mimetics In Adsupporting

confidence: 56%

Regulation of neuronal autophagy and cell survival by MCL1 in Alzheimer’s disease

Rezaeian

Wei

Inuzuka

2022

Acta Materia Medica

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Maintaining neuronal integrity and function requires precise mechanisms controlling organelle and protein quality. Alzheimer’s disease (AD) is also characterized by functional defects in the clearance and recycling of intracellular components. In fact, neuronal homeostasis involves autophagy, mitophagy, apoptosis, and compromised activity in these cellular processes may cause pathological phenotypes of AD. Therefore, mitophagy is a critical mitochondrial quality-control system, and impaired mitophagy is a hallmark of AD. Myeloid cell leukemia 1 (MCL1), a member of the pro-survival B-cell lymphoma protein 2 (BCL2) family, is a mitochondrially targeted protein that contributes to maintaining mitochondrial integrity. Mcl1-knockout mice display peri-implantation lethality. Studies on conditional Mcl1-knockout mice have demonstrated that MCL1 plays a central role in neurogenesis and neuronal survival during brain development. Accumulating evidence indicates the critical role of MCL1 as a regulator of neuronal autophagy, mitophagy, and survival. In this review, we discuss the emerging neuroprotective function of MCL1 and how dysregulation of MCL1 signaling is involved in the pathogenesis of AD. Because members of the pro-survival BCL2 family proteins are promising targets of pharmacological intervention with BH3 mimetic drugs, we also discuss the promise of MCL1-targeting therapy in AD.

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Section: Targeting Of Mcl1 With Bh3 Mimetics In Adsupporting

confidence: 56%

Regulation of neuronal autophagy and cell survival by MCL1 in Alzheimer’s disease

Rezaeian

Wei

Inuzuka

2022

Acta Materia Medica

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“…Here MCL1 and other anti-apoptotic Bcl-2 family members, with the exception of BCL-2 itself, inhibit mitophagy through the inhibition of Parkin translocation to depolarized mitochondria 97 . Furthermore, the selective elimination of damaged mitochondria was enhanced by BH3-mimetic ABT-737, which targets BCL2, BCLxL, and BCLW and UMI-77, which is an MCL1-specific inhibitor [97][98][99] . More recently, mitochondrial dysfunction and mitophagy pathways have a been evaluated as therapeutic targets in Alzheimer's Disease, highlighting a novel therapeutic area of BH3 mimetics in neurodegenerative diseases 98,99 .…”

Section: Mcl1 Regulates Autophagy and Mitophagy Through Bh3-like Protein Interactionsmentioning

confidence: 99%

The multiple mechanisms of MCL1 in the regulation of cell fate

Widden

Placzek

2021

Commun Biol

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MCL1 (myeloid cell leukemia-1) is a widely recognized pro-survival member of the Bcl-2 (B-cell lymphoma protein 2) family and a promising target for cancer therapy. While the role MCL1 plays in apoptosis is well defined, its participation in emerging non-apoptotic signaling pathways is only beginning to be appreciated. Here, we synthesize studies characterizing MCL1s influence on cell proliferation, DNA damage response, autophagy, calcium handling, and mitochondrial quality control to highlight the broader scope that MCL1 plays in cellular homeostasis regulation. Throughout this review, we discuss which pathways are likely to be impacted by emerging MCL1 inhibitors, as well as highlight non-cancerous disease states that could deploy Bcl-2 homology 3 (BH3)-mimetics in the future.

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“…A sublethal dose of UMI-77 enhances this interplay to activate mitophagy without disrupting normal mitochondria and markedly improves Alzheimer's disease pathologies in APP/PS1 mouse model. 17,18 In this study, we used UMI-77 to induce mitophagy in TECs and found that the activation of mitophagy alleviated mitochondrial dysfunction, suppressed TGF-β1/Smad signaling, and blunted inflammation, thus retarding the development of renal fibrosis in unilateral ureteral obstruction (UUO) mice.…”

Section: Introductionmentioning

confidence: 99%

Mitophagy induced by UMI‐77 preserves mitochondrial fitness in renal tubular epithelial cells and alleviates renal fibrosis

Jin

Liu

et al. 2022

The FASEB Journal

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Renal fibrosis is the final common outcome of chronic kidney disease (CKD), which remains a huge challenge due to a lack of targeted treatment. Growing evidence suggests that during the process of CKD, the integrity and function of mitochondria in renal tubular epithelial cells (TECs) are generally impaired and strongly connected with the progression of renal fibrosis. Mitophagy, a selective form of autophagy, could remove aberrant mitochondria to maintain mitochondrial homeostasis. Deficiency of mitophagy has been reported to aggravate renal fibrosis. However, whether induction of mitophagy could alleviate renal fibrosis has not been stated. In this study, we explored the effect of mitophagy activation by UMI‐77, a compound recently verified to induce mitophagy, on murine CKD model of unilateral ureteral obstruction (UUO) in vivo and TECs in vitro. In UUO mice, we found the changes of mitochondrial damage, ROS production, transforming growth factor (TGF)‐β1/Smad pathway activation, as well as epithelial–mesenchymal transition phenotype and renal fibrosis, and these changes were ameliorated by mitophagy enhancement using UMI‐77. Moreover, TEC apoptosis, nuclear factor (NF)‐κB signaling activation, and interstitial inflammation after UUO were significantly mitigated by augmented mitophagy. Then, we found UMI‐77 could effectively and safely induce mitophagy in TECs in vitro, and reduced TGF‐β1/Smad signaling and downstream profibrotic responses in TGF‐β1‐treated TECs. These changes were restored by a mitophagy inhibitor. In conclusion, we demonstrated that mitophagy activation protected against renal fibrosis through improving mitochondrial fitness, downregulating TGF‐β1/Smad signaling and alleviating TEC injuries and inflammatory infiltration in kidneys.

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Targeting MCL1 to induce mitophagy is a potential therapeutic strategy for Alzheimer disease

Cited by 20 publications

References 1 publication

Regulation of neuronal autophagy and cell survival by MCL1 in Alzheimer’s disease

Regulation of neuronal autophagy and cell survival by MCL1 in Alzheimer’s disease

The multiple mechanisms of MCL1 in the regulation of cell fate

Mitophagy induced by UMI‐77 preserves mitochondrial fitness in renal tubular epithelial cells and alleviates renal fibrosis

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