Oxidative regulation of TDP-43 self-association by a β-to-α conformational switch DOI Creative Commons
Jinge Gu, Xiaoming Zhou, Lillian B. Sutherland

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(41)

Published: Oct. 2, 2023

An evolutionarily conserved region of the TDP-43 low-complexity domain (LCD) twenty residues in length can adopt either an α-helical or β-strand conformation. When latter conformation, self-associates via formation a labile, cross-β structure. Self-association be monitored phase-separated protein droplets. Exposure droplets to hydrogen peroxide leads oxidation methionine distributed throughout LCD. Oxidation disassembles structure, thus eliminating both self-association and phase separation. Here, we demonstrate that this process reciprocally enables structure precisely same formerly functioning facilitate β-strand-mediated self-association. We further observe conformation allows interaction with lipid-like detergent exposure lipids enhances β-to-α conformational switch. hypothesize regulation oxidative switch will prove important control localized translation within vertebrate cells. The experimental observations reported herein were heavily reliant on studies 1,6-hexanediol, chemical agent selectively dissolves labile structures formed domains low sequence complexity. This aliphatic alcohol is shown exert its dissociative activity primarily hydrogen-bonding interactions carbonyl oxygen atoms polypeptide backbone. Such underscore central importance backbone-mediated protein:protein separation LCDs.

Language: Английский

Mitochondria at the crossroads of health and disease DOI Creative Commons
Anu Suomalainen, Jodi Nunnari

Cell, Journal Year: 2024, Volume and Issue: 187(11), P. 2601 - 2627

Published: May 1, 2024

Mitochondria reside at the crossroads of catabolic and anabolic metabolism—the essence life. How their structure function are dynamically tuned in response to tissue-specific needs for energy, growth repair, renewal is being increasingly understood. respond intrinsic extrinsic stresses can alter cell organismal by inducing metabolic signaling within cells distal tissues. Here, we review how centrality mitochondrial functions manifests health a broad spectrum diseases aging.

Language: Английский

Citations

110
Mitochondrial protein transport: Versatility of translocases and mechanisms DOI Creative Commons
Jakob D. Busch, Laura F. Fielden, Nikolaus Pfanner

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(6), P. 890 - 910

Published: March 1, 2023

Language: Английский

Citations

84
Mitochondria and cell death DOI
Hannah L. Glover, Annabell Schreiner, Grant Dewson

et al.

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(9), P. 1434 - 1446

Published: June 20, 2024

Language: Английский

Citations

83
A mitochondrial SCF‐FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease DOI Open Access
Yu Cao, Jing Zheng,

Huayun Wan

et al.

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

Published: March 10, 2023

Language: Английский

Citations

68
Stay in touch with the endoplasmic reticulum DOI Open Access
Sha Sun,

Zhao Gan,

Mingkang Jia

et al.

Science China Life Sciences, Journal Year: 2024, Volume and Issue: 67(2), P. 230 - 257

Published: Jan. 4, 2024

Language: Английский

Citations

24
Mitochondrial protein import stress DOI
Nikolaus Pfanner, Fabian den Brave, Thomas Becker

et al.

Nature Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Language: Английский

Citations

3
Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase DOI Creative Commons
Helene Jahn,

Ladislav Bartoš,

Grace I. Dearden

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 8, 2023

Mitochondria are double-membrane-bounded organelles that depend critically on phospholipids supplied by the endoplasmic reticulum. These lipids must cross outer membrane to support mitochondrial function, but how they do this is unclear. We identify Voltage Dependent Anion Channel (VDAC), an abundant protein, as a scramblase-type lipid transporter catalyzes entry. On reconstitution into vesicles, dimers of human VDAC1 and VDAC2 catalyze rapid transbilayer translocation mechanism unrelated their channel activity. Coarse-grained molecular dynamics simulations reveal scrambling occurs at specific dimer interface where polar residues induce large water defects bilayer thinning. The rate phospholipid import yeast mitochondria order magnitude lower in absence VDAC homologs, indicating VDACs provide main pathway for Thus, isoforms, members superfamily beta barrel proteins, moonlight class scramblases - distinct from alpha-helical scramblase proteins act mitochondria.

Language: Английский

Citations

30
Mitochondrial carrier 1 (MTCH1) governs ferroptosis by triggering the FoxO1-GPX4 axis-mediated retrograde signaling in cervical cancer cells DOI Creative Commons
Xuan Wang, Yuting Ji,

Jingyi Qi

et al.

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(8)

Published: Aug. 8, 2023

Abstract Cervical cancer is one of the leading causes death in women. Mitochondrial-mediated ferroptosis (MMF) a recently discovered form cell death. However, role and underlying mechanism MMF cervical remain elusive. Here, using an unbiased screening for mitochondrial transmembrane candidates, we identified carrier 1 ( MTCH1 ) as central mediator cancers. -deficiency disrupted oxidative phosphorylation while elevated reactive oxygen species (ROS) by decreasing NAD + levels. This autonomous event initiated mitochondria-to-nucleus retrograde signaling involving reduced FoxO1 nuclear translocation subsequently downregulation transcription activity key anti-ferroptosis enzyme glutathione peroxidase 4 (GPX4), thereby elevating ROS ultimately triggering ferroptosis. Strikingly, targeting combination with Sorafenib effectively synergistically inhibited growth nude mouse xenograft model actively inducing In conclusion, these findings enriched our understanding mechanisms which governed though to FoxO1-GPX4 axis, provided potential therapeutic target treating cancer.

Language: Английский

Citations

29
EMC rectifies the topology of multipass membrane proteins DOI Creative Commons
Haoxi Wu, Luka Smalinskaitė, Ramanujan S. Hegde

et al.

Nature Structural & Molecular Biology, Journal Year: 2023, Volume and Issue: 31(1), P. 32 - 41

Published: Nov. 13, 2023

Most eukaryotic multipass membrane proteins are inserted into the of endoplasmic reticulum. Their transmembrane domains (TMDs) thought to be co-translationally as they emerge from a membrane-bound ribosome. Here we find that TMDs near carboxyl terminus mammalian post-translationally by reticulum protein complex (EMC). Site-specific crosslinking shows EMC's cytosol-facing hydrophilic vestibule is adjacent pre-translocated C-terminal tail. EMC-mediated insertion mostly agnostic TMD hydrophobicity, favored for short uncharged C-tails and stimulated preceding unassembled bundle. Thus, can released ribosome-translocon in an incompletely state, requiring separate post-translational step rectify their topology, complete biogenesis evade quality control. This sequential co-translational mechanism may apply ~250 diverse proteins, including subunits pentameric ion channel family crucial neurotransmission.

Language: Английский

Citations

29
Mechanism of signal-anchor triage during early steps of membrane protein insertion DOI Creative Commons
Haoxi Wu, Ramanujan S. Hegde

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(6), P. 961 - 973.e7

Published: Feb. 9, 2023

Most membrane proteins use their first transmembrane domain, known as a signal anchor (SA), for co-translational targeting to the endoplasmic reticulum (ER) via recognition particle (SRP). The SA then inserts into using either Sec61 translocation channel or ER protein complex (EMC) insertase. How EMC and collaborate ensure insertion in correct topology is not understood. Using site-specific crosslinking, we detect pre-insertion intermediate adjacent EMC. This forms after release from SRP but before ribosome transfer Sec61. polypeptide's N-terminal tail samples cytosolic vestibule bordered by EMC3, where it can translocate across concomitant with insertion. docks on Sec61, which has an opportunity insert those SAs skipped These results suggest that acts between triage during biogenesis.

Language: Английский

Citations

26