bims-lypmec 2026-07-12 papers

Aging Cell. 2026 Jul;25(7): e70624

Metabolic Kinases as Regulators of Inter-Organelle Communication in Aging and Age-Related Diseases.

Md Riad Chowdhury, Jae-Han Jeon, Dipanjan Chanda.

Cellular aging is accompanied by progressive alterations in metabolic homeostasis, stress adaptation, and organelle function. Increasing evidence suggests that functional coordination among membrane-bound organelles, including mitochondria, the endoplasmic reticulum (ER), lysosomes, peroxisomes, and the Golgi apparatus, contributes to cellular homeostasis during aging. However, the mechanisms linking kinase signaling to specific inter-organelle contact sites or communication pathways remain incompletely defined. In this review, we discuss current evidence linking major metabolic and stress-responsive kinases, including AMPK, pyruvate dehydrogenase kinases (PDKs), mTOR, AKT, and PERK, to organelle coordination in aging and age-related diseases. These kinases regulate mitochondrial dynamics, metabolic flux, calcium and lipid handling, autophagy, lysosomal function, proteostasis, and vesicular trafficking. In some contexts, kinase signaling intersects with defined organelle interfaces, such as mitochondria-associated ER membranes, whereas in many cases the effects on inter-organelle communication are indirect or inferred from broader changes in organelle function. We further discuss how kinase dysregulation may contribute to age-associated defects in mitochondria-ER, mitochondria-lysosome, mitochondria-peroxisome, and ER-Golgi coordination in neurodegeneration, cardiometabolic disease, cellular senescence, and inflammaging. By distinguishing direct contact-site regulation from indirect functional coordination, this review highlights kinase-regulated organelle communication as an emerging, but still incompletely resolved, framework for understanding cellular decline during aging.

Keywords: age‐related diseases; aging; inter‐organelle communication; metabolic kinases; mitochondrial quality control

DOI: https://doi.org/10.1111/acel.70624

Autophagy. 2026 Jul 06. 1-23

Targeting lysosomes with a novel chloroquine derivative induces irreversible lysosomal damage and disrupts autophagosome and lysosome assembly in cancer.

Nitish Chauhan, Ananda Guha Majumdar, Sujit Kumar Bhutia, Papiya Dey, Mahesh Subramanian, Birija Sankar Patro.

Pancreatic ductal adenocarcinoma (PDAC) exhibits profound therapy resistance driven by lysosome-dependent nutrient recycling, metabolic adaptation, and stress tolerance. Current lysosome targeting agents such as chloroquine (CQ)/hydroxychloroquine (HCQ) show limited efficacy due to transient activity and dose-limiting-toxicities. To overcome these limitations, we developed lysostilbenes, a new class of hybrid small molecules combining the CQ pharmacophore with lysosome-disrupting stilbene analogs. Stilbene pharmacophore is the core structural component of resveratrol. Among the synthesized hybrids, lysostilbene-4 emerged as the lead candidate, demonstrating ~30-40-fold greater cytotoxicity against PDAC cells than parent compounds, while sparing nonmalignant cells. At nanomolar concentrations, lysostilbene-4 induced rapid, irreversible lysosomal membrane permeabilization (LMP), initiating a lysosome mitochondria apoptotic cascade via CTSB (cathepsin B) release, BID cleavage, BAX activation, and caspase-mediated apoptosis. In parallel, it abrogated lysosomal recovery by significantly reducing repair, lysophagy, autophagosome maturation, and uncoupling TFEB-driven transcriptional programs from effective lysosome biogenesis. Reduced TFEB mRNA expression correlated with poor overall-survival and disease-free-survival across multiple cancer patients, with a particularly strong association in pancreatic cancer patients. Using TFEB+/+ and TFEB-/- knockout pancreatic cancer cells we establish that lysostilbene-4 exerts severe cytotoxicity by inducing persistent lysosomal-damage and disrupting autophagosome-lysosome assembly, with vulnerability further amplified in TFEB-deficient cells. This finding underscores TFEB as a key determinant of lysosomal-resilience and a potential predictive biomarker. Importantly, lysostilbene-4 was well tolerated in preclinical mouse-models at supra-therapeutic doses without systemic-toxicity. These findings position lysostilbene-4 as a first-in-class lysosome-targeting therapeutic that enforces sustained lysosomal collapse while compromising adaptive recovery-mechanisms, providing a mechanistically precise and safe strategy against PDAC.Abbreviations: ALG: autophagy-lysosome genes; AMPK: AMP-activated protein kinase; CASM: conjugation of ATG8s to single membranes; CTSB: cathepsin B; LGALS3: galectin 3; LMP: lysosomal membrane permeabilization; LS: lysostilbene; MTOR: mechanistic target of rapamycin kinase; PDAC: pancreatic ductal adenocarcinoma; TCGA: The Cancer Genome Atlas; TFEB: transcription factor EB; ULK1: unc-51 like autophagy activating kinase 1.

Keywords: Chloroquine; dihydroxystilbene; lysophagy; lysosome repair; lysostilbene; resveratrol

DOI: https://doi.org/10.1080/15548627.2026.2693263

Traffic. 2026 Sep;27(3): e70042

Syntaxin 12 Sustains Endosomal-Lysosomal Homeostasis and Survival in Glioblastoma Stem-Like Cells.

Clément Maghe, Agnieszka Barbach, Gwennan André-Grégoire, Clotilde C N Renaud, Margaux Le Guyon, Rosalie Moreau, Nicolas Bidère, Julie Gavard.

Glioblastoma cells display a striking vulnerability to disruptions in late endosome-lysosome trafficking, a dependency that we exploited through a targeted siRNA screen in patient-derived cells with stem-like properties (GSCs). This screen identified Syntaxin 12 (STX12) as a critical determinant of GSC survival. Originally characterized as a recycling endosome t-SNARE, STX12 regulates tubular recycling and retrograde transport, yet its broader implications for lysosomal homeostasis remain poorly understood. Functional characterization revealed that STX12 is required to maintain lysosomal organization in GSCs, consistent with its known roles as an endosomal t-SNARE. Loss of STX12 altered dynamic processes that support GSC fitness, culminating in controlling life-and-death decisions. Because lysosomal function is deeply connected with the autophagic pathway, we next explored whether STX12 contributes to this adaptive program. STX12 silencing produced signatures consistent with impaired endo-lysosomal progression and disrupted mechanistic target of rapamycin (mTOR)/lysosome communication. This work further identifies a previously unrecognized role for STX12 in the adaptive trafficking network that supports glioblastoma cell survival, revealing a potential SNARE-centered vulnerability for therapeutic intervention.

Keywords: cell death; endo‐lysosome; glioblastoma; lysosomes; mTOR signaling; recycling; trafficking

DOI: https://doi.org/10.1111/tra.70042

J Cell Biol. 2026 Sep 07. pii: e202511211. [Epub ahead of print]225(9):

Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.

Emily Glover, Beth Wiseman, Celyn Dugdale, Charlie Humphery, Lorena Sueiro Ballesteros, Lorna Hodgson, Kevin Wilkinson, Ian Collinson.

Mitochondrial protein import is critical for organelle biogenesis, maintenance, and regeneration-essential for cellular homeostasis. Import dysfunction compromises cellular energy supplies, which is damaging to cells, particularly those with high energetic demands like neurons. Previously, we have shown that import failure is rescued by intercellular mitochondrial transfer (IMT) via tunnelling nanotubes (TNTs) however, the fate of the transferred mitochondria and the mechanistic basis for rescue were unresolved. Here, we show that bidirectional mitochondrial trafficking between cells harboring import-defective and import-competent mitochondria is distinct in terms of their regulation and ensuing consequences. Transferred import-defective mitochondria are highly fragmented and destined for canonical lysosomal degradation. In contrast, reactive oxygen species (ROS)-producing mitochondria at the periphery of cells with import-competent mitochondria are transferred into neighboring cells undergoing import failure. These new arrivals then accumulate within previously uncharacterized "mitochondrial degradation bodies" (MDBs). We speculate that the cooperation of these distinct cases of TNT-mediated conventional and noncanonical "trans-mitophagy" instigates mitochondrial regeneration, and thereby rescues mitochondrial function.

DOI: https://doi.org/10.1083/jcb.202511211

Front Cardiovasc Med. 2026 ;13 1872513

Calcium dysregulation in diabetic cardiomyopathy & heart failure with preserved ejection fraction.

Anza Ali, Vineet M Sharma, Yuriana Aguilar-Sanchez.

Diabetes is a major risk factor for cardiovascular disease, and heart failure (HF), particularly heart failure with preserved ejection fraction (HFpEF), which is the most prevalent form of HF in patients with type 2 diabetes (T2D). However, the mechanisms behind diabetes-induced cardiomyopathy (DbCM) are complex and remain poorly understood. Insulin resistance resulting from diabetes has been shown to contribute to cardiac impairment, leading to diastolic dysfunction and hypertrophy. Studies have shown that the impairment of calcium (Ca2+)-handling cardiac proteins, such as sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) and ryanodine receptor type 2 (RyR2), may act as key drivers behind the development of DbCM and its progression to HF. However, further studies are needed to fully understand their impact. This review focuses on the intersection of diabetes and HFpEF at the molecular level, showing how insulin resistance contributes to cardiac impairment, and the critical role of Ca2+ -handling proteins in DbCM progression. Due to the limited understanding and the complexity of DbCM, there are currently no viable cures that reverse disease progression in DbCM or HFpEF. However, adeno-associated virus (AAV)- mediated gene therapies show promise for treating diabetes-induced cardiomyopathy. This review discusses molecular pathways affected under DbCM and HFpEF conditions as well as potential treatments in both preclinical and clinical trials to analyze their effectiveness.

Keywords: Ca2+ dysregulation; Ca2+ handling; HFpEF; diabetic cardiomyopathy; gene therapy

DOI: https://doi.org/10.3389/fcvm.2026.1872513