FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors

The EMBO Journal, Год журнала: 2023, Номер 42(13)

Опубликована: Май 10, 2023

Abstract To maintain both mitochondrial quality and quantity, cells selectively remove damaged or excessive mitochondria through mitophagy, which is a specialised form of autophagy. Mitophagy induced in response to diverse conditions, including hypoxia, cellular differentiation damage. However, the mechanisms that govern removal specific dysfunctional under steady‐state conditions fine‐tune content are not well understood. Here, we report SCF FBXL4 , an SKP1/CUL1/F‐box protein ubiquitin ligase complex, localises outer membrane unstressed mediates constitutive ubiquitylation degradation mitophagy receptors NIX BNIP3 suppress basal levels mitophagy. We demonstrate pathogenic variants cause encephalopathic mtDNA depletion syndrome (MTDPS13) do efficiently interact with core machinery mediate BNIP3. Thus, reveal molecular mechanism whereby actively suppresses by preventing accumulation. propose dysregulation turnover causes FBXL4‐associated syndrome.

Язык: Английский

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Mitophagy mediated by BNIP3 and NIX protects against ferroptosis by downregulating mitochondrial reactive oxygen species

Cell Death and Differentiation, Год журнала: 2024, Номер 31(5), С. 651 - 661

Опубликована: Март 22, 2024

Язык: Английский

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Cardiovascular disease: Mitochondrial dynamics and mitophagy crosstalk mechanisms with novel programmed cell death and macrophage polarisation

Pharmacological Research, Год журнала: 2024, Номер 206, С. 107258 - 107258

Опубликована: Июнь 21, 2024

Several cardiovascular illnesses are associated with aberrant activation of cellular pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis and macrophage polarisation as hallmarks contributing to vascular damage abnormal cardiac function. Meanwhile, these three novel forms dysfunction closely related mitochondrial homeostasis. Mitochondria the main organelles that supply energy maintain Mitochondrial stability is maintained through a series regulatory pathways, such fission, fusion mitophagy. Studies have shown (e.g., impaired dynamics mitophagy) promotes ROS production, leading oxidative stress, which induces M1 phenotypic polarisation. Therefore, an in-depth knowledge dynamic regulation mitochondria during necessary understand disease development. This paper systematically summarises impact changes in mitophagy on regulating dysfunctions promote understanding pathogenesis diseases provide corresponding theoretical references for treating diseases.

Язык: Английский

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FBXL4 mutations cause excessive mitophagy via BNIP3/BNIP3L accumulation leading to mitochondrial DNA depletion syndrome

Cell Death and Differentiation, Год журнала: 2023, Номер 30(10), С. 2351 - 2363

Опубликована: Авг. 11, 2023

Язык: Английский

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Nix interacts with WIPI2 to induce mitophagy

The EMBO Journal, Год журнала: 2023, Номер 42(22)

Опубликована: Авг. 25, 2023

Nix is a membrane-anchored outer mitochondrial protein that induces mitophagy. While has an LC3-interacting (LIR) motif binds to ATG8 proteins, it also contains minimal essential region (MER) mitophagy through unknown mechanism. We used chemically induced dimerization (CID) probe the mechanism of Nix-mediated and found both LIR MER are required for robust find interacts with autophagy effector WIPI2 recruits mitochondria. The converts homogeneous distribution on surface mitochondria into puncta, even in absence ATG8s. Together, this work reveals unanticipated mechanisms Nix-induced elusive role MER, while describing interesting example induction acts downstream canonical initiation complexes.

Язык: Английский

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Upregulated pexophagy limits the capacity of selective autophagy

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 9, 2024

Abstract Selective autophagy is an essential process to maintain cellular homeostasis through the constant recycling of damaged or superfluous components. Over a dozen selective pathways mediate degradation diverse substrates, but whether these can influence one another remains unknown. We address this question using pexophagy, autophagic peroxisomes, as model. show in cells that upregulated pexophagy impairs both mitochondria and protein aggregates by exhausting initiation factor, ULK1. confirm finding cell models pexophagy-mediated form Zellweger Spectrum Disorder, disease characterized peroxisome dysfunction. Further, we extend generalizability limited determining increased aggregate reciprocally reduces Parkinson’s Disease Huntington’s Disease. Our findings suggest degradative capacity become increase substrate.

Язык: Английский

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Loss of WIPI4 in neurodegeneration causes autophagy-independent ferroptosis

Nature Cell Biology, Год журнала: 2024, Номер 26(4), С. 542 - 551

Опубликована: Март 7, 2024

Abstract β-Propeller protein-associated neurodegeneration (BPAN) is a rare X-linked dominant disease, one of several conditions that manifest with and brain iron accumulation. Mutations in the WD repeat domain 45 ( WDR45 ) gene encoding WIPI4 lead to loss function BPAN but cellular mechanisms how these trigger pathology are unclear. The prevailing view literature simply consequence autophagy deficiency given functions this degradation pathway. However, our data indicate depletion causes ferroptosis—a type cell death induced by lipid peroxidation—via an autophagy-independent mechanism, as demonstrated both culture zebrafish. increases ATG2A localization at endoplasmic reticulum–mitochondrial contact sites, which enhances phosphatidylserine import into mitochondria. This results increased mitochondrial synthesis phosphatidylethanolamine, major prone peroxidation, thus enabling ferroptosis. mechanism has minimal overlap classical ferroptosis stimuli provides insights may provide clues for therapeutic strategies.

Язык: Английский

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Targeting selective autophagy and beyond: From underlying mechanisms to potential therapies

Journal of Advanced Research, Год журнала: 2024, Номер 65, С. 297 - 327

Опубликована: Май 14, 2024

Autophagy is an evolutionarily conserved turnover process for intracellular substances in eukaryotes, relying on lysosomal (in animals) or vacuolar yeast and plants) mechanisms. In the past two decades, emerging evidence suggests that, under specific conditions, autophagy can target particular macromolecules organelles degradation, a termed selective autophagy. Recently, accumulating studies have demonstrated that abnormality of closely associated with occurrence progression many human diseases, including neurodegenerative cancers, metabolic cardiovascular diseases. This review aims at systematically comprehensively introducing its role various while unravelling molecular mechanisms By providing theoretical basis development related small-molecule drugs as well treating this seeks to contribute understanding therapeutic potential. review, we introduce dissect major categories been discovered. We also focus recent advances underlying both classical non-classical Moreover, current situation targeting different types further summarized, valuable insights into discovery more candidate future. On other hand, reveal clinically relevant implementations are potentially autophagy, such predictive approaches treatments tailored individual patients.

Язык: Английский

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Physiological functions of ULK1/2

Journal of Molecular Biology, Год журнала: 2024, Номер 436(15), С. 168472 - 168472

Опубликована: Фев. 2, 2024

UNC-51-like kinases 1 and 2 (ULK1/2) are serine/threonine that best known for their evolutionarily conserved role in the autophagy pathway. Upon sensing nutrient status of a cell, ULK1/2 integrate signals from upstream cellular energy sensors such as mTOR AMPK relay them to downstream components machinery. also play indispensable roles selective pathway, removing damaged mitochondria, invading pathogens, toxic protein aggregates. Additional functions have emerged beyond autophagy, including trafficking, RNP granule dynamics, signaling events impacting innate immunity, axon guidance, homeostasis, cell fate. Therefore, it is no surprise alterations expression activity been linked with pathophysiological processes, cancer, neurological disorders, cardiovascular diseases. Growing evidence suggests function biological rheostats, tuning intra extra-cellular cues. Given broad physiological relevance, candidate targets small molecule activators or inhibitors may pave way development therapeutics treatment diseases humans.

Язык: Английский

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Reconstitution of BNIP3/NIX-mediated autophagy reveals two pathways and hierarchical flexibility of the initiation machinery

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 28, 2024

Selective autophagy is a lysosomal degradation pathway that critical for maintaining cellular homeostasis by disposing of harmful material. While the mechanisms which soluble cargo receptors recruit machinery are becoming increasingly clear, principles governing how organelle-localized transmembrane initiate selective remain poorly understood. Here, we demonstrate can autophagosome biogenesis not only recruiting upstream FIP200/ULK1 complex but also via WIPI-ATG13 complex. This latter employed BNIP3/NIX to trigger mitophagy. Additionally, other mitophagy receptors, including FUNDC1 and BCL2L13, exclusively use complex, while FKBP8 ER-phagy receptor TEX264 capable utilizing both pathways autophagy. Our study defines molecular rules initiation revealing remarkable flexibility in assembly activation machinery, with significant implications therapeutic interventions.

Язык: Английский

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