bims-lypmec 2026-04-05 papers

bims-lypmec

Biomed News

on Lysosomal positioning and metabolism in cardiomyocytes

Issue of 2026–04–05
seven papers selected by
Satoru Kobayashi, New York Institute of Technology

Lysosome: a critical hub for ferroptosis regulation.
Dual pathways of TFEB activation under lysosomal stress: ATG conjugation-dependent and -independent modes.
Lysosomal homeostasis at the crossroads of neurodegeneration.
Lipid turnover and GEF recruitment collectively determine Rab5 recruitment and activation during the first step of early endosome formation.
Intercompartmental communication in senescence.
Mitochondrial dysfunction in diabetic cardiomyopathy: a review of pathogenic mechanisms and therapeutic strategies.
TFEB degradation is regulated by an IKK/β-TrCP2 phosphorylation-ubiquitination cascade.

Trends Cell Biol. 2026 Mar 30. pii: S0962-8924(26)00038-3. [Epub ahead of print]

Lysosome: a critical hub for ferroptosis regulation.

Xin Chen.

  Ferroptosis is an iron-dependent programmed cell death that involves lipid peroxidation. Ferroptosis represents a critical process underlying tumorigenesis and multiple pathological disorders. Recently, lysosomes have been found to orchestrate ferroptotic signaling, linking iron metabolism, oxidative homeostasis, and selective autophagy. Furthermore, lysosomal membrane disruption leads to the release of intraluminal iron and cathepsins, thereby facilitating ferroptotic damage, whereas lysosomal exocytosis acts in the opposite direction to limit ferroptosis. Therefore, pharmacological modulation of lysosomal activities could be used to treat drug-resistant tumors or protect normal tissues against ferroptosis-related injuries. In this review, we summarize how lysosomes control ferroptosis, focusing on the regulation through lysosomal contents, pH, degradation processes, and exocytosis. We also discuss possible therapeutics that target lysosomes to modulate ferroptosis-associated diseases.

Keywords:  LMP; autophagy; ferritinophagy; ferroptosis; iron; lysosome

DOI:  https://doi.org/10.1016/j.tcb.2026.03.007
Autophagy. 2026 Mar 30. 1-3

Dual pathways of TFEB activation under lysosomal stress: ATG conjugation-dependent and -independent modes.

Takayuki Shima, Shuhei Nakamura.

  TFEB (transcription factor EB) regulates the expression of autophagy and lysosomal genes, is activated by various cellular stresses, and plays a key role in maintaining cellular homeostasis. Recent work demonstrates that TFEB is activated during lysosomal damage through two distinct mechanisms: ATG conjugation-dependent and -independent. TFEB activation proceeds sequentially through two modes. In the early ATG conjugation-independent mode (Mode I), APEX1 interacts with TFEB in the nucleus, maintaining its transcriptional activity and protein stability. In the later ATG conjugation-dependent mode (Mode II), CCT7 and TRIP6 translocate to lysosomes and interact with TFEB, modulating its phosphorylation and nuclear localization. Moreover, TFEB regulation induced by other cellular stresses-such as oxidative stress, proteasome inhibition, mitochondrial damage, and DNA damage-also involves either Mode I or Mode II. Our findings provide new insights into a unified understanding of TFEB regulation under diverse cellular stress conditions.

Keywords:  Damage; TFEB; lysosome; mitochondria; organelle

DOI:  https://doi.org/10.1080/15548627.2026.2642336
J Clin Invest. 2026 Apr 01. pii: e199845. [Epub ahead of print]136(7):

Lysosomal homeostasis at the crossroads of neurodegeneration.

Stefano De Tito, Sharon A Tooze.

Lysosomes function as metabolic control centers that integrate degradation, nutrient sensing, and stress signaling. In neurons, which must maintain proteostasis and energetic balance throughout life, lysosomal homeostasis determines cellular resilience. Emerging evidence identifies lysosomal injury and defective repair as common denominators across neurodegenerative diseases. Damage to the lysosomal membrane caused by oxidative stress, lipid imbalance, or genetic mutations triggers a hierarchical quality control cascade. Early lesions recruit the endosomal sorting complex required for transport (ESCRT) machinery for mechanical resealing, while larger ruptures activate lipid-centered recovery modules. When repair fails, lysophagy eliminates irreparable organelles and a TFEB-dependent transcriptional program regenerates the lysosomal pool. These tightly coupled responses safeguard neurons from catastrophic proteostatic collapse. Their impairment, through mutations in lysosomal proteins, or through aging, produces the lysosomal fragility that underlies Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis/frontotemporal dementia, and Huntington disease. Crosstalk between lysosomes, mitochondria, and ER integrates local damage with systemic metabolic adaptation, while dysregulated lysosomal exocytosis and inflammation propagate pathology. Understanding how ESCRT complexes, lipid transport, and transcriptional renewal cooperate to preserve lysosomal integrity reveals unifying principles of neurodegeneration and defines molecular targets for intervention. Restoring lysosomal repair and renewal offers a rational path toward preventing neuronal loss.

DOI: https://doi.org/10.1172/JCI199845
Nat Commun. 2026 Mar 30.

Lipid turnover and GEF recruitment collectively determine Rab5 recruitment and activation during the first step of early endosome formation.

Yongtao Du, Xilin Miao, Yu Gao, Yu Liang, Xue Bai, Song Dang, Zhongsheng Wu, Zhengyang An, Xinyi Zhang, Yaran Yang, Zhe Zhang, Huaqing Cai, Kangmin He.

Early endosomes are the pivotal sorting station in eukaryotic cells. A longstanding critical question is how the small GTPase Rab5 is precisely targeted to the correct membrane to initiate early endosome formation. Here, we identify Rabex5 and hRME6 as the two guanine-nucleotide exchange factors (GEFs) that together regulate Rab5 recruitment during early endosome formation. Single-molecule imaging of genome-edited cells reveals that Rabex5 and hRME6 are recruited continuously or transiently to nascent uncoated endocytic carriers, respectively. However, in contrast to uncoated endocytic carriers and other intracellular organelles, directing Rabex5 or its GEF domain to clathrin-coated pits or the plasma membrane fails to trigger Rab5 recruitment. Both in vivo and in vitro experiments show that the plasma membrane-enriched phospholipid PI(4,5)P2 prevents Rab5 association with the plasma membrane. Importantly, we found that impaired hydrolysis of PI(4,5)P2 led to reduced early endosome formation in Lowe syndrome cells. Therefore, the spatiotemporal recruitment and activation of Rab5 during early endosome formation are collectively determined by Rabex5/hRME6 recruitment and PI(4,5)P2 depletion during uncoated endocytic carrier formation.

DOI: https://doi.org/10.1038/s41467-026-70543-8
FEBS Open Bio. 2026 Mar 30.

Intercompartmental communication in senescence.

Krystyna Mazan-Mamczarz, Eleanor J Wind, Jixiang Leng, Myriam Gorospe.

  Cellular senescence represents a response to sublethal damage, characterized by persistent growth arrest and a robust pro-inflammatory trait, the senescence-associated secretory phenotype (SASP). Senescent cells accumulate in the body with age, promoting tissue dysfunction and age-related disease. In addition to profound reprogramming of gene expression patterns, senescent cells undergo broad remodeling of cellular compartments, including the plasma membrane, nucleus, endoplasmic reticulum (ER), Golgi apparatus, endolysosomal system, mitochondria, biomolecular condensates, and cytoskeleton. These changes alter the intracellular communication networks required for homeostasis. Here, we review how senescence alters (i) vesicular trafficking along secretory, endocytic, and autophagic routes, (ii) interorganelle contact sites such as those among mitochondria, ER, and lysosomes to modulate lipid and calcium exchange, and (iii) diffusion and transport of regulatory signals across the cytosol and membranes. We discuss how the impaired crosstalk among compartments increases ROS, exacerbates proteostatic stress, impairs clearance of damaged components, and activates p53/p21, p16/Rb, cGAS-STING, NF-κB, and mTOR pathways, enhancing apoptosis resistance and the SASP. Finally, we highlight emerging technologies to study the senescent organelle 'interactome' and identify therapeutic vulnerabilities in age-associated declines and diseases linked to senescence. Impact statement We synthesize evidence that cellular senescence arises not only from gene expression changes but also from disrupted interorganelle communication. We discuss defects in vesicle trafficking and organelle contact sites that redefine senescence as failure of the organellar interactome, highlighting future mechanistic work and therapeutic opportunities in age-related disease.

Keywords:  Golgi; SASP; endoplasmic reticulum; interorganellar communication; organelles; senescence

DOI:  https://doi.org/10.1002/2211-5463.70236
Front Cardiovasc Med. 2026 ;13 1751243

Mitochondrial dysfunction in diabetic cardiomyopathy: a review of pathogenic mechanisms and therapeutic strategies.

Yulian Huang, Qiao Ma, Wei Wang, Shanjun Huang, Jianqiang Zhao.

  Diabetic cardiomyopathy (DCM) presents a significant clinical challenge, independently contributing to heart failure morbidity and mortality in patients with diabetes mellitus. Although advancements in glycemic control and cardiovascular therapies have been made, effective strategies specifically addressing DCM remain limited, highlighting the urgent need to clarify its underlying pathogenesis. Recent research has increasingly recognized mitochondrial dysfunction as a central driver of DCM, linking metabolic derangements, oxidative stress, inflammation, and programmed cell death into a complex pathological network. This review critically examines recent experimental and clinical findings to delineate the multidimensional mechanisms by which mitochondrial impairment propels DCM progression. We specifically explore alterations in energy metabolism, excessive reactive oxygen species (ROS) production, inflammasome activation, and dysregulation of apoptotic and ferroptotic pathways. Additionally, we summarize the latest advances in mitochondria-targeted therapeutic strategies, including small molecule antioxidants, metabolic modulators, gene-based therapies, stem cell-derived exosomes, and lifestyle interventions aimed at restoring mitochondrial health. Finally, we briefly highlight future research directions, emphasizing the potential of multi-targeted interventions and emerging technologies such as single-cell transcriptomics to deepen mechanistic insights. A comprehensive understanding of mitochondrial-centered pathways may offer promising avenues for innovative therapies and improved clinical outcomes in DCM.

Keywords:  cell death; diabetic cardiomyopathy; metabolic remodeling; mitochondrial dysfunction; oxidative stress; targeted interventions

DOI:  https://doi.org/10.3389/fcvm.2026.1751243
Nat Commun. 2026 Apr 01.

TFEB degradation is regulated by an IKK/β-TrCP2 phosphorylation-ubiquitination cascade.

Yan Xiong, Jaiprakash Sharma, Meggie N Young, Wen Xiong, Ali Jazayeri, Karl F Poncha, Ma Xenia G Ilagan, Qing Wang, Bei Gao, Hui Zheng, Nicolas L Young, Marco Sardiello.

Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and cellular clearance pathways. TFEB activity is tightly controlled by multiple post-translational mechanisms, but the exact molecular mechanism controlling its stability has remained elusive. Here, we identify the IκB kinase (IKK) complex as a key regulator of TFEB protein stability through a phosphorylation-ubiquitination cascade. A high-content kinase inhibitor screen reveals that IKK inhibition increases TFEB protein levels, and genetic ablation of IKK components increases TFEB stability, upregulates lysosomal genes, and enhances lysosomal biogenesis and degradative capacity. Mechanistically, we show that IKK phosphorylates TFEB on a cluster of serine residues (423SPFPSLS429), generating a phosphodegron recognized by the E3 ligase β-TrCP2, which in turn targets TFEB for proteasomal degradation via ubiquitination of adjacent lysine residues (K430 and K431). Mutation of either the phosphosites or the ubiquitination sites stabilizes TFEB without impairing its ability to translocate to the nucleus, activate target gene expression, or promote tau clearance in a cell model of tauopathy. These findings establish IKK-β-TrCP2 as a core regulatory axis controlling TFEB protein turnover and levels and reveal a mechanistically distinct layer of TFEB regulation that may be leveraged to enhance lysosomal function in disease contexts.

DOI: https://doi.org/10.1038/s41467-026-71001-1