bims-lypmec 2026-06-07 papers

Nature. 2026 Jun 03.

LASER couples damage sensing to ESCRT assembly for lysosome repair.

Claire S Goul, Aakriti Jain, Samira Yitiz, Zahra E Soltani, Serim Yang, Simon Rapp, Martina Spacci, Scot Federman, James Sacco, Huinan Li, Lauren D Enriquez, Nalan Liv, Laralynne Przybyla, Roberto Zoncu.

Lysosomal membrane integrity is essential for cell survival, but how damage sensing is spatiotemporally coupled to repair remains poorly understood. Recruitment and assembly of endosomal sorting complex required for transport (ESCRT) I-III rapidly counteracts membrane damage, but it is unclear how ESCRT-I recognizes defective lysosomal membranes. Here, leveraging genome-wide CRISPRi screens in a damage-sensitized genetic background, we identified LC3/GABARAP-assisted stimulator for ESCRT recruitment (LASER), a multicomponent protein assembly that forms rapidly upon calcium release from damaged lysosomes and couples sensing of lysosomal membrane damage to ESCRT-dependent repair. At the core of LASER is TFG, an endoplasmic reticulum exit-site-resident protein that translocates to damaged lysosomes by binding to ATG8 family proteins (LC3 and GABARAP) conjugated to lysosomal phospholipids. ATG8-bound TFG forms oligomeric assemblies that directly recruit the essential ESCRT-I subunit TSG101 via conserved motif recognition enhanced by avidity-driven interactions. TFG binding to TSG101 stimulates sequential ESCRT-I-II-III polymerization and promotes membrane repair. TFG mutations that drive hereditary spastic paraplegia disrupt its oligomerization and impair lysosomal ESCRT recruitment and membrane resealing, implicating defective repair as a driver of TFG-associated neurodegeneration. Thus, LASER promotes ESCRT polymerization at damaged lysosomes and couples damage sensing to membrane repair.

DOI: https://doi.org/10.1038/s41586-026-10604-6

J Neurosci. 2026 Jun 04. pii: e2214252026. [Epub ahead of print]

Late Endosome Transport by RILP-RAB7A Promotes Dendrite Arborization Independently of Degradation.

Chan Choo Yap, Laura Digilio, Lloyd P McMahon, Ryan J Mulligan, Isabelle F Witteveen, Bettina Winckler.

Directional dendritic transport of late endosomes (LEs) retrogradely towards the soma is required for fusion with lysosomes and for degradation in the soma. Both dendritic motility of LEs and somatic degradation require RAB7A. Similarly, interference with dynein function reduces motility of LEs and results in degradative failure. Blocking dynein function also impairs normal dendrite growth, suggesting that motility of LEs and subsequent fusion with lysosomes might be required for dendrite growth. RAB7A and dynein are mechanistically linked via the dynein-interacting RAB7A effector RILP. RILP also binds the LE-lysosome fusion tether HOPS. In non-neuronal cells, downregulation of RILP leads to impaired degradation due to deficiencies in LE transport and fusion defects with lysosomes. In this work, we express a separation-of-function mutant of RAB7A (RAB7A-L8A) incapable of RILP binding. Based on the results in non-neuronal cells, we hypothesized that both endosome motility and degradation in neurons depended on RILP. Our data in cultured rat and mouse hippocampal neurons of both sexes suggest that endogenous RILP is a functional RAB7A-dependent dynein adaptor for LE motility in dendrites. In addition, it promotes endosome carrier formation. As a consequence of LE transport inhibition, degradative cargos are not cleared normally from dendrites in RAB7A-L8A. Surprisingly, lysosomal fusion and somatic degradation do not require RAB7A-RILP interactions. Despite the normal degradation, dendrite arborization is impaired in RAB7A-L8A expressing neurons, demonstrating that dendrite morphology defects are separable from degradation blockade. This indicates that normal dendrite growth/maintenance is dependent on sustained RAB7A/RILP-dependent LE transport.Significance Statement Dendrite growth requires membrane trafficking, but the roles of individual compartments and regulators are not well established. Stunted dendrite growth is often associated with endolysosomal traffic jams and degradation block. In contrast, our work reveals a requirement for transport of late endosomes via RAB7A-RILP to support dendrite growth independently of cargo transport to the lysosome for degradation.

DOI: https://doi.org/10.1523/JNEUROSCI.2214-25.2026

J Cell Biol. 2026 Aug 03. pii: e202511088. [Epub ahead of print]225(8):

A cytosolic IF1 reporter enables real-time visualization of severe mitochondrial membrane damage.

Erqing Gao, Liwei Guan, Kehang Zhang, Shuze Qi, Jingxiu Xu, Jie Zhang, Tianyi Zhu, Bing Yang, Chonglin Yang, Eric Miska, Mao Zhang, Suhong Xu.

Maintenance of mitochondrial integrity is fundamental for cellular survival, yet how cells recognize catastrophic mitochondrial membrane damage remains unknown. Here, we identify MAI-1 as the first genetically encoded reporter of severe mitochondrial membrane damage. MAI-1 is a Caenorhabditis elegans homolog of the ATP synthase inhibitor IF1 that lacks a mitochondrial targeting sequence, resides in the cytosol under basal conditions, but rapidly and irreversibly translocates to severely damaged mitochondria within milliseconds. We validate MAI-1 across diverse injury paradigms and demonstrate that cytosolic IF1 variants from other species exhibit conserved damage-induced recruitment. Mechanistically, MAI-1 recruitment requires the presence of an intact ATP synthase complex. Using MAI-1 as a sensor, we uncover that these severely damaged mitochondria are cleared through the LGG-1-mediated, PINK1/PARKIN-independent lysosomal pathway. Together, our findings establish a powerful tool for visualizing severe mitochondrial membrane damage and reveal a surveillance mechanism dedicated to structural integrity control.

DOI: https://doi.org/10.1083/jcb.202511088

Free Radic Biol Med. 2026 Jun 03. pii: S0891-5849(26)00848-8. [Epub ahead of print]

Plasma - Activated Medium Engages Redox Signaling to Activate a VDAC1-TRPML1 Lysosomal-Mitochondrial Ca2+ Death Pathway.

Pengpeng Huang, Yan Zheng, Chuanzan Zhou, Chengbiao Ding, Qi Zhang, Dechao Feng, Zhengwei Wu.

Plasma-activated medium (PAM), a redox-active anticancer modality, induces cytotoxicity in multiple tumor models, but the mechanisms underlying PAM-induced tumor cell death remain incompletely understood. Here, using A549 lung cancer cells together with additional tumor models, we identify a lysosome - mitochondria Ca2+ circuit that drives a distinct form of PAM-induced tumor-selective cell death. PAM promotes the coupling of the lysosomal Ca2+ channel TRPML1 to the mitochondrial outer membrane protein VDAC1 at organelle contact sites, leading to lysosomal Ca2+ release, mitochondrial Ca2+ overload, membrane depolarization, cytochrome c release, and cell death. Mechanistically, PAM suppresses mTORC2 - SGK1 signaling, reduces VDAC1 phosphorylation at Ser104, and stabilizes VDAC1 on mitochondria. Accumulated VDAC1 then engages TRPML1 through Lys109 and Arg163 to facilitate pathological Ca2+ transfer. Disrupting this interface, or restoring phosphomimetic control of VDAC1, attenuated mitochondrial Ca2+ overload, improved cell survival, and weakened the antitumor effect of PAM in vivo. Pan-cancer analyses further suggested that although high VDAC1 expression is associated with poor prognosis, it may help stratify tumors more likely to respond to PAM. Together, these findings establish the VDAC1 - TRPML1 axis as a key mechanistic link between PAM-induced redox stress and lysosome - mitochondria Ca2+-dependent tumor cell death, and highlight this pathway as a potential therapeutic target and response biomarker.

Keywords: Mitochondria; Mitochondrial calcium overload; Plasma Activated Medium; Ubiquitination; VDAC1-TRPML1 interaction sites; lysosome crosstalk

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.06.003