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

PINK1 regulated mitophagy is evident in skeletal muscles DOI Creative Commons
François Singh, Léa P. Wilhelm, Alan R. Prescott

et al.

Autophagy Reports, Journal Year: 2024, Volume and Issue: 3(1)

Published: March 11, 2024

PINK1, mutated in familial forms of Parkinson's disease, initiates mitophagy following mitochondrial depolarization. However, it is difficult to monitor this pathway physiologically mice as loss PINK1 does not alter basal levels most tissues. To further characterize vivo, we used mito-QC which was combined with the mitochondrial-associated POLGD257A mutation. We focused on skeletal muscle gene expression data indicates that tissue has highest levels. found oxidative hindlimb significantly reduced mitophagy. Of interest, presence mutation, while having a minor effect tissues, restored caused by PINK1. Although our observations highlight multiple pathways operate within single tissue, identify choice for study PINK1-dependant under conditions.

Language: Английский

Citations

9
Reconstitution of BNIP3/NIX-mediated autophagy reveals two pathways and hierarchical flexibility of the initiation machinery DOI Creative Commons
Elias Adriaenssens, Stefan Schaar, Annan SI Cook

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 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.

Language: Английский

Citations

9
Pexophagy and Oxidative Stress: Focus on Peroxisomal Proteins and Reactive Oxygen Species (ROS) Signaling Pathways DOI Creative Commons
Xiaofan Wei,

Laxman Manandhar,

Hyunsoo Kim

et al.

Antioxidants, Journal Year: 2025, Volume and Issue: 14(2), P. 126 - 126

Published: Jan. 23, 2025

Peroxisomes generate reactive oxygen species (ROS) and also play a role in protecting cells from the damaging effects of such radicals. Dysfunctional peroxisomes are recognized by receptors degraded selective type macroautophagy called pexophagy. Oxidative stress is one signals that activates pexophagy through multiple signaling pathways. Conversely, impaired results accumulation damaged peroxisomes, which turn leads to elevated ROS levels oxidative stress, resulting as cellular dysfunction progression diseases neurodegeneration, cancer, metabolic disorders. This review explores molecular mechanisms driving its regulation with particular focus on ROS. highlights peroxisomal proteins ROS-mediated pathways regulating In addition, emerging evidence suggests dysregulation closely linked neurological disorders, underscoring potential therapeutic target. Understanding intricate crosstalk between provides new insights into maintenance homeostasis offers promising directions for addressing disorders tightly associated stress.

Language: Английский

Citations

1
Diverse routes to mitophagy governed by ubiquitylation and mitochondrial import DOI Creative Commons
Michael J. Clague, Sylvie Urbé

Trends in Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

HighlightsStructural and biochemical studies of PINK1 activation stabilisation have captured TOM complex interactions the formation a PINK1–TOM–TIM supercomplex.USP30 inhibition shows promising preclinical indications.FBXL4 is major suppressor NIX/BNIP3-dependent mitophagy.PPTC7 scaffolds interaction FBXL4–SCF ligase with BNIP3 NIX.Control PPTC7 mitochondrial import sets levels NIX.AbstractThe selective removal mitochondria by mitophagy proceeds via multiple mechanisms essential for human well-being. The PINK1/Parkin NIX/BNIP3 pathways are strongly linked to dysfunction hypoxia, respectively. Both regulated ubiquitylation import. Recent elucidated how ubiquitin kinase acts as sensor stress through stable supercomplex. stability NIX SCFFBXL4 complex. Substrate recognition requires an adaptor molecule, PPTC7, whose availability limited Unravelling functional implications each mode remains critical challenge. We propose that prompts switch between these two pathways.

Language: Английский

Citations

1
When autophagy meets placenta development and pregnancy complications DOI Creative Commons
Pei Zhou, Junqi Wang, Jun Wang

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: Feb. 2, 2024

Autophagy is a common biological phenomenon in eukaryotes that has evolved and reshaped to maintain cellular homeostasis. Under the pressure of starvation, hypoxia, immune damage, autophagy provides energy nutrients cells, which benefits cell survival. In mammals, an early embryonic nutrient supply system involved development, implantation, pregnancy maintenance. Recent studies have found imbalance placental tissue plays key role occurrence development complications, such as gestational hypertension, obesity, premature birth, miscarriage, intrauterine growth restriction. This mini-review summarizes molecular mechanism regulation, pathways, related factors comprehensively describes complications.

Language: Английский

Citations

7
RNF31 alleviates liver steatosis by promoting p53/BNIP3-related mitophagy in hepatocytes DOI
Yifei Chen,

Fuji Yang,

Yujie Shi

et al.

Free Radical Biology and Medicine, Journal Year: 2024, Volume and Issue: 219, P. 163 - 179

Published: April 13, 2024

Language: Английский

Citations

7
Segregation of pathways leading to pexophagy DOI Creative Commons
Francesco G. Barone, Sylvie Urbé, Michael J. Clague

et al.

Life Science Alliance, Journal Year: 2023, Volume and Issue: 6(5), P. e202201825 - e202201825

Published: Feb. 21, 2023

Peroxisomes are organelles with key roles in metabolism including long-chain fatty acid production. Their metabolic functions overlap and interconnect those of mitochondria, which they share an overlapping but distinct proteome. Both degraded by selective autophagy processes termed pexophagy mitophagy. Although mitophagy has received intense attention, the pathways linked to associated tools less well developed. We have identified neddylation inhibitor MLN4924 as a potent activator show that this is mediated HIF1α-dependent up-regulation BNIP3L/NIX, known adaptor for pathway from induced USP30 deubiquitylase CMPD-39, we identify NBR1 central player. Our work suggests level complexity regulation peroxisome turnover includes capacity coordinate mitophagy, via NIX, acts rheostat both processes.

Language: Английский

Citations

16
The interplay between mitophagy and mitochondrial ROS in acute lung injury DOI

Yizhi Zhong,

Siwei Xia,

Gaojian Wang

et al.

Mitochondrion, Journal Year: 2024, Volume and Issue: 78, P. 101920 - 101920

Published: June 12, 2024

Language: Английский

Citations

6
Opposing roles for AMPK in regulating distinct mitophagy pathways DOI Creative Commons

Marianna Longo,

Aniketh Bishnu,

Pierpaolo Risiglione

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(22), P. 4350 - 4367.e9

Published: Nov. 1, 2024

Mitophagy degrades damaged mitochondria, but we show here that it can also target functional mitochondria. This latter scenario occurs during programmed mitophagy and involves the receptors NIX BNIP3. Although AMP-activated protein kinase (AMPK), energy-sensing kinase, influence damaged-induced mitophagy, its role in is unclear. We found AMPK directly inhibits NIX-dependent by triggering 14-3-3-mediated sequestration of ULK1, via ULK1 phosphorylation at two sites: Ser556 an additional identified site, Ser694. By contrast, activation increases Parkin enhances rate depolarization-induced independently ULK1. this happens both cultured cells tissues vivo, using mito-QC mouse model. Our work unveils a mechanism whereby downregulates mitochondria dysfunctional/damaged ones.

Language: Английский

Citations

6
A genome-wide screen links peroxisome regulation with Wnt signaling through RNF146 and TNKS/2 DOI Creative Commons
Jonathan T. Vu, Katherine U. Tavasoli, Connor J. Sheedy

et al.

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(10)

Published: July 5, 2024

Peroxisomes are membrane-bound organelles harboring metabolic enzymes. In humans, peroxisomes required for normal development, yet the genes regulating peroxisome function remain unclear. We performed a genome-wide CRISPRi screen to identify novel factors involved in peroxisomal homeostasis. found that inhibition of RNF146, an E3 ligase activated by poly(ADP-ribose), reduced import proteins into peroxisomes. RNF146-mediated loss depended on stabilization and activity poly(ADP-ribose) polymerases TNKS TNKS2, which bind membrane protein PEX14. propose RNF146 TNKS/2 regulate efficiency PARsylation at membrane. Interestingly, we increased RNF146-dependent degradation non-peroxisomal substrates, including β-catenin destruction complex component AXIN1, was sufficient alter amplitude transcription. Together, these observations not only suggest previously undescribed roles regulation but also role bridging with Wnt/β-catenin signaling during development.

Language: Английский

Citations

5