bims-lypmec 2026-10-25 papers

J Cell Biol. 2026 Nov 02. pii: e202511137. [Epub ahead of print]225(11):

ClC-7 links PIKfyve inhibition to Rab-dependent LRRK2 activity at lysosomes.

Devin Clegg, Amanda Bentley-DeSousa, Agnes Roczniak-Ferguson, Shawn M Ferguson.

Increased activity of leucine-rich repeat kinase 2 (LRRK2) confers Parkinson's disease risk. LRRK2 dynamically localizes to lysosomal membranes in response to various stresses, yet the mechanisms by which distinct lysosomal perturbations are communicated to LRRK2 remain unclear. Here, we show that inhibition of the lysosomal lipid kinase PIKfyve promotes LRRK2 recruitment and signaling through a pathway that requires the lysosomal chloride/proton antiporter ClC-7. ClC-7 in turn controls the accumulation of multiple Rab GTPases on lysosomes. LRRK2 signaling under these conditions requires its established Rab-binding surfaces, with Rab12 contributing significantly to this response. This pathway operates independently of CASM. In contrast, lysosomal stresses that induce CASM require both Rab-binding sites on LRRK2 and GABARAP for robust LRRK2 signaling. These findings identify ClC-7-dependent lysosomal remodeling and Rab accumulation as key features linking PIKfyve inhibition to LRRK2 signaling and reveal that distinct lysosomal stresses engage different combinations of Rab and GABARAP inputs to activate LRRK2.

DOI: https://doi.org/10.1083/jcb.202511137

Traffic. 2026 Dec;27(4): e70056

The Lysosomal Clock: Are We Only as Old as Our Lysosomes?

Alexis Diaz Vegas, Thierry Galli.

Lysosomes are a major organelle involved in intracellular degradation, membrane traffic and metabolic signaling, but how their biochemical composition changes during normal aging remains poorly defined. Puszynska and colleagues now combine lysosome purification with metabolomics and lipidomics across tissues, species and ages to reveal a conserved signature of lysosomal aging characterized by accumulation of glycerophosphodiesters (GPDs) and cystine and remodeling of bis(monoacylglycero)phosphate (BMP). Strikingly, these changes are largely obscured in whole-tissue analyses and resemble metabolic abnormalities associated with lysosomal storage disorders, including CLN3 disease and cystinosis. The signature develops progressively with age, can predict chronological age, and is attenuated by caloric restriction in peripheral tissues but not in the brain. Within the brain, age-dependent metabolite accumulation is particularly prominent in microglia and is also detected in neurons, linking lysosomal aging to cell populations central to neurodegenerative disease. These findings define an organelle-level metabolic clock, suggesting that one might be only as young as one's lysosomes. Establishing whether GPDs, cystine and BMP remodeling merely mark lysosomal age or actively contribute to declining lysosomal degradation and membrane traffic may uncover a metabolic connection between physiological aging, lysosomal storage disorders and vulnerability to late-onset neurodegeneration.

DOI: https://doi.org/10.1111/tra.70056

J Cell Biol. 2026 Nov 02. pii: e202610007. [Epub ahead of print]225(11):

Swollen lysosomes grab Rabs for a CASM-free route to LRRK2 activation.

Suzanne R Pfeffer.

Multiple lysosomal stresses activate Parkinson's-linked LRRK2 kinase, and these involve the so-called "CASM" pathway to help recruit LRRK2 to lysosome surfaces. Clegg et al. (https://doi.org/10.1083/jcb.202511137) show that LRRK2, activated upon lysosome swelling caused by PIKfyve inhibition, instead relies solely on Rab GTPase binding for lysosome localization and activation.

DOI: https://doi.org/10.1083/jcb.202610007

Mol Pharm. 2026 Oct 05. 23(10): 4949-4959

SLC46A3 Mediates Lysosomal Egress of Auristatin Derivatives.

Naoki Saito, Naotaka Takahashi, Ryuto Tomabechi, Hiroyuki Kusuhara, Akiko Kyoya, Kaori Nakazawa, Mariko Kondo, Hiroaki Iwasa, Hisanao Kishimoto, Kei Higuchi, Katsuhisa Inoue.

The lysosomal transporter SLC46A3 has been implicated in the pharmacology of antibody-drug conjugates (ADCs) by facilitating the transport of payloads from lysosomes to the cytosol. To date, two payload classes, maytansinoid catabolites (e.g., DM1 and Lys-SMCC-DM1) and the pyrrolobenzodiazepine (PBD) dimer SG3199, have been identified as SLC46A3 substrates; however, the transport mechanisms for other payloads remain to be elucidated. Auristatin derivatives (auristatins) are among the most widely deployed payloads in approved ADCs, yet the mechanism by which these highly potent peptides egress from the lysosome remains unclear. Here, we demonstrate that SLC46A3 directly transports auristatins. At pH 5.0, mimicking the lysosomal environment, SLC46A3 significantly facilitated the membrane transport of all tested auristatins, whereas transport via passive diffusion was negligible. Among the auristatins, monomethyl auristatin F (MMAF), which bears a negative charge, was a superior substrate for SLC46A3 compared to monomethyl auristatin E (MMAE), a finding consistent with the preference of SLC46A3 for organic anions. Interestingly, MMAF conjugated with a non-cleavable maleimidocaproyl (mc) linker, was also recognized as an SLC46A3 substrate, exhibiting higher transport activity than unmodified MMAF. Furthermore, depletion of SLC46A3 in HER2-positive cancer cells attenuated the cytotoxicity of trastuzumab-mcMMAF, suggesting that SLC46A3 mediates the lysosomal egress of its active metabolites. Taken together, our findings highlight lysosomal transporters including SLC46A3, as critical determinants of the efficient cytoplasmic release of auristatins, providing an opportunity to optimize ADC efficacy.

Keywords: ADC; SLC46A3; auristatins; lysosome; payload

DOI: https://doi.org/10.1021/acs.molpharmaceut.6c00535

Clin Transl Med. 2026 Oct;pii: e70876. [Epub ahead of print]16(10):

Lysosomal protein transmembrane 5 protects against myocardial ischemia-reperfusion injury by promoting mitophagy via the NEDD4-LC3 axis.

Yadan Zhang, Qingqing Wu, Yang Xiao, Ying Liu, Qi Yao, Jiabin Yu, Shasha Wang, Si Chen, Xiaofeng Zeng, Qizhu Tang.

BACKGROUND: Mitophagy is essential for mitochondrial quality control during myocardial ischemia-reperfusion (I/R) injury. Lysosomal protein transmembrane 5 (LAPTM5) has been implicated in cardiovascular disease and autophagy, but its role in cardiac mitophagy remains unclear.
METHODS: LAPTM5 knockout mice and cardiomyocyte-targeted AAV9-cTnT-LAPTM5 were used to determine the role of LAPTM5 in myocardial I/R injury. Cardiomyocyte hypoxia/reoxygenation models, mt-Keima imaging, mitochondrial fractionation, LC3-mitochondrial colocalization, co-immunoprecipitation, molecular docking, site-directed mutagenesis, NEDD4 gain- and loss-of-function, and p62 ubiquitination assays were used to investigate the underlying mechanism. Depending on data distribution and group number, appropriate parametric or non-parametric statistics were applied together with correction for multiple testing.
RESULTS: LAPTM5 expression progressively decreased following I/R or H/R stress. LAPTM5 deficiency aggravated myocardial injury, cardiac dysfunction, and mitochondrial structural and functional damage, whereas LAPTM5 overexpression attenuated these abnormalities. LAPTM5 promoted mitophagy by enhancing LC3 recruitment to mitochondria. Mechanistically, LAPTM5 recruited NEDD4 to mitochondria through its PY3 motif and facilitated NEDD4-LC3 complex formation. NEDD4 depletion abolished LAPTM5-mediated mitophagy and cytoprotection, whereas re-expression of NEDD4-WT, but not the E3-inactive NEDD4-CS mutant, restored these effects. NEDD4-WT also increased p62 ubiquitination. AAV9-mediated LAPTM5 re-expression reduced infarct size, improved cardiac function, and preserved mitochondrial integrity in LAPTM5-deficient hearts.
CONCLUSIONS: LAPTM5 protects against myocardial I/R injury by promoting mitophagy through the NEDD4-LC3 axis. PY3-dependent recruitment of NEDD4 and its E3 ubiquitin ligase activity facilitate LC3-associated mitochondrial clearance, accompanied by enhanced p62 ubiquitination, thereby preserving mitochondrial homeostasis during reperfusion.

Keywords: LAPTM5; cardioprotection; heart; ischemia/reperfusion; mitophagy

DOI: https://doi.org/10.1002/ctm2.70876

Circ Res. 2026 Oct 23. 139(10): e329682

Saving the Capillaries: FGFR1/KLB and MFG-E8 in Diabetic Hearts.

Mahmoud H Elbatreek, David J Lefer.

Keywords: Editorials; diabetes mellitus; fibrosis; heart failure; microcirculation

DOI: https://doi.org/10.1161/CIRCRESAHA.126.329682