PPTC7 acts as an essential co-factor of the SCFFBXL4 ubiquitin ligase complex to restrict BNIP3/3L-dependent mitophagy DOI Creative Commons

Xiayun Xu,

Yingji Chen,

Sishi Fei

et al.

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 1, 2025

Abstract Mitophagy is a selective process that targets the damaged, dysfunctional, or superfluous mitochondria for degradation through autophagy. The SCF FBXL4 E3 ubiquitin ligase complex suppresses basal mitophagy by targeting BNIP3 and BNIP3L, two key cargo receptors, ubiquitin-proteasomal degradation. loss-of-function mutations lead to excessive BNIP3/3L-dependent mitophagy, thereby causing devastating multi-system disorder called mitochondrial DNA depletion syndrome, type 13 (MTDPS13). PPTC7, matrix phosphatase, essential proper function biogenesis. Here, we show proportion of PPTC7 located on outer membrane, where it interacts with BNIP3/3L. decreases BNIP3/3L protein stability in phosphatase activity-independent manner. Using vitro cell culture Pptc7 knockout mouse model, demonstrate deficiency activates high levels Mechanistically, facilitates -mediated Overall, these findings establish as an co-factor suppressor mitophagy.

Language: Английский

FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors DOI Creative Commons
Giang Nguyen, Keri‐Lyn Kozul, Yi Cui

et al.

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(13)

Published: May 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.

Language: Английский

Citations

48
Mitophagy mediated by BNIP3 and NIX protects against ferroptosis by downregulating mitochondrial reactive oxygen species DOI
Shun‐ichi Yamashita, Yuki Sugiura, Yuta Matsuoka

et al.

Cell Death and Differentiation, Journal Year: 2024, Volume and Issue: 31(5), P. 651 - 661

Published: March 22, 2024

Language: Английский

Citations

22
Cardiovascular disease: Mitochondrial dynamics and mitophagy crosstalk mechanisms with novel programmed cell death and macrophage polarisation DOI Creative Commons
Dandan Liu,

Hewei Qin,

Yang Gao

et al.

Pharmacological Research, Journal Year: 2024, Volume and Issue: 206, P. 107258 - 107258

Published: June 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.

Language: Английский

Citations

22
FBXL4 mutations cause excessive mitophagy via BNIP3/BNIP3L accumulation leading to mitochondrial DNA depletion syndrome DOI
Yingji Chen, Dongyue Jiao, Yang Liu

et al.

Cell Death and Differentiation, Journal Year: 2023, Volume and Issue: 30(10), P. 2351 - 2363

Published: Aug. 11, 2023

Language: Английский

Citations

29
Nix interacts with WIPI2 to induce mitophagy DOI Creative Commons
Eric Bunker, François Le Guerroué, Chunxin Wang

et al.

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(22)

Published: Aug. 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.

Language: Английский

Citations

24
TNIP1 inhibits selective autophagy via bipartite interaction with LC3/GABARAP and TAX1BP1 DOI
François Le Guerroué, Eric Bunker, William M. Rosencrans

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(6), P. 927 - 941.e8

Published: March 1, 2023

Language: Английский

Citations

23
Targeting selective autophagy and beyond: From underlying mechanisms to potential therapies DOI Creative Commons
Wei Ma, Yingying Lü, Xin Jin

et al.

Journal of Advanced Research, Journal Year: 2024, Volume and Issue: 65, P. 297 - 327

Published: May 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.

Language: Английский

Citations

12
Upregulated pexophagy limits the capacity of selective autophagy DOI Creative Commons
Kyla Germain, Raphaella W. L. So, Laura F. DiGiovanni

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 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.

Language: Английский

Citations

11
Loss of WIPI4 in neurodegeneration causes autophagy-independent ferroptosis DOI Creative Commons

Ye Zhu,

Motoki Fujimaki,

Louisa Snape

et al.

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(4), P. 542 - 551

Published: March 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.

Language: Английский

Citations

11
Physiological functions of ULK1/2 DOI Creative Commons
Gautam Pareek,

Mondira Kundu

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: 436(15), P. 168472 - 168472

Published: Feb. 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.

Language: Английский

Citations

9