bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2025–09–28
thirteen papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Ubiquitination-activated TAB-TAK1-IKK-NF-κB axis modulates gene expression for cell survival in the lysosomal damage response.
  2. Lysosomes signal through the epigenome to regulate longevity across generations.
  3. Isolation of functional lysosomes from skeletal muscle.
  4. The heart of diabetes: unraveling metabolic drivers of cardiomyopathy.
  5. JIP4 and RILPL1 utilize opposing motor force to dynamically regulate lysosomal tubulation.
  6. The Role of the Beclin1 Complex in Rab9-Dependent Alternative Autophagy.
  7. The interplay of the cGAS-STING pathway with the lysosome.
  8. Lysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism.
  9. The Impact of PCSK9 on Diabetic Cardiomyopathy: Mechanisms and Implications.
  10. Mitochondria expel tainted DNA - spurring age-related inflammation.
  11. Sex-related differences of diabetic cardiomyopathy.
  12. Emerging roles of TRIM in metabolic regulation.
  13. Rebalancing cardiolipin biosynthesis to treat cardiomyopathy.
  1. Elife. 2025 Sep 24. pii: RP106901. [Epub ahead of print]14
    Ubiquitination-activated TAB-TAK1-IKK-NF-κB axis modulates gene expression for cell survival in the lysosomal damage response.
    Akinori Endo, Chikage Takahashi, Naoko Ishibashi, Yasumasa Nishito, Koji Yamano, Keiji Tanaka, Yukiko Yoshida.
      The lysosomal damage response is important for the maintenance of cellular homeostasis in human cells. Although the mechanisms underlying the repair and autophagic elimination of damaged lysosomes have been elucidated, the early signal transduction pathways and genes induced in response to lysosomal damage remain elusive. We performed transcriptome and proteome analyses and found that the TAB-TAK1-IKK-NF-κB axis is activated by K63-linked ubiquitin chains that accumulate on damaged lysosomes. This activates the expression of various transcription factors and cytokines that promote anti-apoptosis and intercellular signaling. The findings highlight the crucial role of ubiquitin-regulated signal transduction and gene expression in cell survival and cell-cell communication in response to lysosomal damage. The results suggest that the ubiquitin system is not only involved in the removal of damaged lysosomes by lysophagy, but also functions in the activation of cellular signaling for cell survival.
    Keywords:  NF-κB; TAB; TAK1; cell biology; human; lysosomal damage response; ubiquitin
    DOI:  https://doi.org/10.7554/eLife.106901
  2. Science. 2025 Sep 25. 389(6767): 1353-1360
    Lysosomes signal through the epigenome to regulate longevity across generations.
    Qinghao Zhang, Weiwei Dang, Meng C Wang.
      The epigenome is sensitive to metabolic inputs and is crucial for aging. Lysosomes act as a signaling hub to sense metabolic cues and regulate longevity. We found that lysosomal metabolic pathways signal through the epigenome to regulate transgenerational longevity in Caenorhabditis elegans. Activation of lysosomal lipid signaling and lysosomal adenosine monophosphate-activated protein kinase (AMPK) or reduction of lysosomal mechanistic target of rapamycin (mTOR) signaling increased the expression of a histone H3.3 variant and increased its methylation on K79, leading to life-span extension across multiple generations. This transgenerational prolongevity effect required intestine-to-germline transportation of histone H3.3 and a germline-specific H3K79 methyltransferase and was recapitulated by overexpressing H3.3 or the H3K79 methyltransferase. Thus, signals from a lysosome affect the epigenome and link the soma and germ line to mediate transgenerational inheritance of longevity.
    DOI:  https://doi.org/10.1126/science.adn8754
  3. Am J Physiol Cell Physiol. 2025 Sep 22.
    Isolation of functional lysosomes from skeletal muscle.
    Thulasi Mahendran, Anastasiya Kuznyetsova, Neushaw Moradi, David A Hood.
      Lysosomes are membrane-bound organelles responsible for the degradation of damaged or dysfunctional cellular components, including mitochondria. Their acidic internal environment and the presence of an array of hydrolytic enzymes facilitate the efficient breakdown of macromolecules such as proteins, lipids, and nucleic acids. Mitochondria play a critical role in maintaining skeletal muscle homeostasis to meet the energy demands under physiological and pathological conditions. Mitochondrial quality control within skeletal muscle during processes such as exercise, disuse, and injury is regulated by mitophagy, where dysfunctional mitochondria are targeted for lysosomal degradation. The limited understanding of quality control mechanisms in skeletal muscle necessitates the need for isolating intact lysosomes to assess organelle integrity and the degradative functions of hydrolytic enzymes. Although several methods exist for lysosome isolation, the complex structure of skeletal muscle makes it challenging to obtain relatively pure and functional lysosomes due to the high abundance of contractile proteins. Here we describe a method to isolate functional lysosomes from small amounts of mouse skeletal muscle tissue, preserving membrane integrity. We also describe functional assays that allow direct evaluation of lysosomal enzymatic activity and we provide data indicating reduced lysosomal degradative activity in lysosomes from aging muscle. We hope that this protocol provides a valuable tool to advance our understanding of lysosomal biology in skeletal muscle, supporting investigations into lysosome-related dysfunction in aging, disease, and exercise adaptations.
    Keywords:  differential centrifugation; lysosomal enzymes; mitochondria; mitophagy; proteolysis
    DOI:  https://doi.org/10.1152/ajpcell.00471.2025
  4. Cardiovasc Diabetol Endocrinol Rep. 2025 Sep 08. 11(1): 18
    The heart of diabetes: unraveling metabolic drivers of cardiomyopathy.
    Xue Guan, Can Zhou, Xinyi Zhuo, Wenhui Yang, Haizhen Wang.
      Diabetes mellitus (DM) ignites a global epidemic, with cardiovascular complications claiming most lives among affected patients. Diabetic cardiomyopathy (DCM), a distinct cardiac dysfunction triggered by DM independent of coronary artery disease or hypertension, threatens those with type 1 or type 2 DM, often leading to heart failure. In type 2 DM (T2DM), metabolic disruptions drive cardiac lipotoxicity. Yet, how lipotoxicity impairs function and DM sparks clinical syndromes remains unclear. This review unveils how DM rewires myocardial metabolism-favoring lipids over glucose-and probes emerging therapies, spotlighting clinical challenges at a vital research frontier.
    DOI:  https://doi.org/10.1186/s40842-025-00231-x
  5. J Cell Biol. 2025 Nov 03. pii: e202404018. [Epub ahead of print]224(11):
    JIP4 and RILPL1 utilize opposing motor force to dynamically regulate lysosomal tubulation.
    Luis Bonet-Ponce, Tsion Tegicho, Nuria Fernandez-Martinez, Irene A Rozenberg, Mia Ashriem, Alexandra Beilina, Jillian H Kluss, Yan Li, Mark R Cookson.
      Lysosomes are dynamic organelles that remodel their membrane in response to stimuli. We previously uncovered a process we term LYsosomal Tubulation/sorting driven by LRRK2 (LYTL), wherein damaged lysosomes generate tubules sorted into vesicles. LYTL is orchestrated by the Parkinson's disease kinase LRRK2 that recruits the motor adaptor protein and RHD family member JIP4 to lysosomes. JIP4 enhances LYTL tubule extension toward the plus-end of microtubules. To identify new players involved in LYTL, we mapped the lysosomal proteome after LRRK2 kinase inhibition. We found that RILPL1 is recruited to dysfunctional lysosomes in an LRRK2 kinase activity-dependent manner, facilitated by pRAB proteins. Unlike JIP4, RILPL1 induces retraction of LYTL tubules by binding to p150Glued, thereby moving lysosomal tubules toward the minus-end of microtubules. Our findings emphasize the dynamic regulation of LYTL tubules by two distinct RHD proteins and pRAB effectors, acting as opposing motor adaptor proteins. These opposing forces create a metastable lysosomal membrane deformation, enabling dynamic tubulation events.
    DOI:  https://doi.org/10.1083/jcb.202404018
  6. Int J Mol Sci. 2025 Sep 19. pii: 9151. [Epub ahead of print]26(18):
    The Role of the Beclin1 Complex in Rab9-Dependent Alternative Autophagy.
    Sohyeon Baek, Yunha Jo, Jihoon Nah.
      Autophagy is a conserved catabolic pathway that degrades intracellular cargo through the lysosomal system. Canonically, this process is orchestrated by the autophagy-related (Atg)5-Atg7 conjugation system, which facilitates the formation of microtubule-associated protein 1 light chain 3 (LC3)-decorated double-membrane vesicles known as autophagosomes. However, accumulating evidence has revealed the existence of an Atg5-Atg7-independent, alternative autophagy pathway that still relies on upstream regulators such as the unc-51 like autophagy activating kinase 1 (Ulk1) kinase and the Beclin1 complex. In this review, we provide a comprehensive overview of the role of the Beclin1 complex in canonical autophagy and highlight its emerging importance in alternative autophagy. Notably, the recent identification of transmembrane protein 9 (TMEM9) as a lysosomal protein that interacts with Beclin1 to promote member RAS oncogene family 9 (Rab9)-dependent autophagosome formation has significantly advanced our understanding of alternative autophagy regulation. Furthermore, this Ulk1-Rab9-Beclin1-dependent mitophagy has been shown to mediate to mitochondrial quality control in the heart, thereby contributing to cardioprotection under ischemic and metabolic stress conditions. We further examine how the Beclin1 complex functions as a central scaffold in both canonical and alternative autophagy, with a focus on its modulation by novel factors such as TMEM9 and the potential therapeutic implications of these regulatory mechanisms.
    Keywords:  Beclin1 complex; Rab9; TMEM9; WD-repeat protein, phosphoinositide interacting (Wipis); alternative autophagy; heart diseases
    DOI:  https://doi.org/10.3390/ijms26189151
  7. Trends Biochem Sci. 2025 Sep 23. pii: S0968-0004(25)00218-X. [Epub ahead of print]
    The interplay of the cGAS-STING pathway with the lysosome.
    Yinfeng Xu, Wei Wan.
      The cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon (IFN) genes (STING) pathway detects cytoplasmic DNA and elicits the innate immune response. Several recent studies show that cGAS-STING signaling not only terminates at the lysosome but also regulates lysosomal function. Here, we discuss the interplay of the cGAS-STING pathway with the lysosome.
    Keywords:  ESCRT; STING; TFEB; cGAS; innate immunity; lysosome
    DOI:  https://doi.org/10.1016/j.tibs.2025.08.010
  8. Sci Adv. 2025 Sep 26. 11(39): eadt6366
    Lysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism.
    Ashutosh Kumar, Yonghui Zhao, Litao Xie, Rahul Chadda, John D Tranter, Ryan T Mikami, Nihil Abraham, Juan Hong, Ethan Feng, David R Rawnsley, Haiyan Liu, Kayla M Henry, Gretchen Meyer, Meiqin Hu, Haoxing Xu, Antentor Hinton, Chad E Grueter, E Dale Abel, Andrew W Norris, Abhinav Diwan, Rajan Sah.
      The lysosome integrates anabolic signaling and nutrient sensing to regulate intracellular growth pathways. The leucine-rich repeat-containing 8 (LRRC8) channel complex forms a lysosomal anion channel and regulates PI3K-AKT-mTOR signaling, skeletal muscle differentiation, growth, and systemic glucose metabolism. Here, we define the endogenous LRRC8 subunits localized to a subset of lysosomes in differentiated myotubes. We show that LRRC8A affects leucine-stimulated mTOR; lysosome size; number; pH; expression of lysosomal proteins LAMP2, P62, and LC3B; and lysosomal function. Mutating an LRRC8A lysosomal targeting dileucine motif sequence (LRRC8A-L706A;L707A) in myotubes recapitulates the abnormal AKT signaling and altered lysosomal morphology and pH observed in LRRC8A knockout cells. In vivo, LRRC8A-L706A;L707A knock-in mice exhibit increased adiposity, impaired glucose tolerance and insulin resistance associated with reduced skeletal muscle PI3K-AKT-mTOR signaling, glucose uptake, and impaired incorporation of glucose into glycogen. These data reveal a lysosomal LRRC8-mediated metabolic signaling function regulating lysosomal function, systemic glucose homeostasis, and insulin sensitivity.
    DOI:  https://doi.org/10.1126/sciadv.adt6366
  9. Biomolecules. 2025 Aug 27. pii: 1240. [Epub ahead of print]15(9):
    The Impact of PCSK9 on Diabetic Cardiomyopathy: Mechanisms and Implications.
    Haixia Wang, Pei Wang, Yubo Wang, Shuzhen Du, Jing Zhao, Zheng Zhang.
      Diabetic cardiomyopathy (DCM) is a common and clinically relevant complication of diabetes mellitus, defined by myocardial dysfunction in the absence of overt coronary artery disease or systemic hypertension. Recent studies have identified proprotein convertase subtilisin/kexin type 9 (PCSK9) as a pivotal mediator in the pathogenesis of DCM. PCSK9 contributes not only to dyslipidemia via degradation of LDLR and consequent elevation of circulating LDL-C, but also to metabolic derangements and inflammation through interactions with receptors such as CD36 and Toll-like receptor 4 (TLR4). In DCM, PCSK9 has been shown to exacerbate inflammation and pyroptosis and is closely linked to impaired autophagic function. Elevated circulating PCSK9 has emerged as a potential biomarker for cardiovascular events in patients with type 2 diabetes mellitus (T2DM). At the same time, long-term administration of PCSK9 inhibitors (PCSK9i) has not been associated with a significant increase in incident diabetes. Furthermore, PCSK9 loss-of-function mutations have been linked to a modestly heightened risk of T2DM, underscoring its complex involvement in cardiometabolic regulation and disease. This review synthesizes current insights into the mechanistic and therapeutic roles of PCSK9 in DCM, aiming to inform precision cardiovascular risk management strategies in T2DM populations.
    Keywords:  DCM; NLRP3 inflammasome; PCSK9; PCSK9 inhibitor; inflammatory response; lipid metabolism
    DOI:  https://doi.org/10.3390/biom15091240
  10. Nature. 2025 Sep 26.
    Mitochondria expel tainted DNA - spurring age-related inflammation.
    Gemma Conroy.
      
    Keywords:  Ageing; Cell biology; Genetics; Metabolism
    DOI:  https://doi.org/10.1038/d41586-025-03064-x
  11. Diabetes Res Clin Pract. 2025 Sep 23. pii: S0168-8227(25)00934-9. [Epub ahead of print] 112920
    Sex-related differences of diabetic cardiomyopathy.
    Olivia Zeiler Ell, Annemie S Bojer, Martin H Sørensen, Peter Gæde, Per Lav Madsen.
       AIMS: It is well known that patients with type 2 diabetes (T2D) have an increased risk of both ischemic and non-ischemic heart disease. We studied sex differences in the microvascular function and myocardial extracellular fibrosis that underlie cardiac dysfunction METHODS: In a cross-sectional echocardiography and cardiovascular magnetic resonance imaging study, myocardial extracellular volume fraction (ECV), myocardial blood flow at rest (MBFrest) and during adenosine-induced stress (MBFstress), and the myocardial perfusion reserve (MPR) were determined in 221 patients with T2D without ischemic heart disease and 25 age-matched controls. We investigated sex-related differences in MBF, MPR, ECV, and diastolic and systolic function.
    RESULTS: Both in unadjusted analyses and after multiple linear regression analyses adjusted for known confounders, women with T2D had higher MBFrest, MBFstress, and ECV than men. The differences in microvascular function resulted in T2D men and women both having lower MPR compared to healthy controls, but the underlying causes differed. Female sex associated with lower lateral e' and higher E/e' independently of MBFstress and ECV.
    CONCLUSIONS: These findings highlight distinct sex-specific mechanisms of microvascular dysfunction and myocardial remodeling in T2D. Recognizing these differences may be critical for improving risk stratification and guiding targeted preventive strategies in diabetic cardiomyopathy.
    Keywords:  Diabetes; Diabetic cardiomyopathy; Fibrosis; Heart failure with preserved ejection fraction; Metabolic heart disease; Myocardial blood flow
    DOI:  https://doi.org/10.1016/j.diabres.2025.112920
  12. Metabolism. 2025 Sep 21. pii: S0026-0495(25)00263-X. [Epub ahead of print]174 156394
    Emerging roles of TRIM in metabolic regulation.
    Jiaxing Wang, Qiangzhou Wang, Xinrui Li, Qingqing Cai, Yulin Bi, Chenyang Xu, Hao Bai, Lihong Gu, Guobin Chang, Shihao Chen.
      Recent findings have broadened our understanding of the tripartite motif (TRIM) protein family, positioning these proteins as pivotal regulators of cellular metabolism and cell fate. Primarily functioning as versatile E3 ubiquitin ligases, TRIM proteins orchestrate key metabolic pathways-including glucose, lipid, and amino acid metabolism-through both ubiquitination-dependent and -independent mechanisms such as oligomerization and epigenetic modification. For example, TRIM38, TRIM11, and TRIM24 have been reported to modulate glycolytic flux and insulin signaling by targeting key glucose transporters and glycolytic enzymes, with effects on cancer metabolism and insulin responses in model systems. Similarly, TRIM21 and TRIM56 have been implicated in fatty acid synthesis, oxidation, and cholesterol balance, with potential relevance to fatty-liver conditions and atherosclerosis. Moreover, TRIM-mediated regulation of amino acid metabolism-particularly through pathways involving glutamine and branched-chain amino acids-plays a central role in tumor metabolic reprogramming and survival. Beyond enzymatic regulation, TRIM proteins exert non-canonical functions through epigenetic modulation and interactions with signaling networks. This review synthesizes current insights into the multifaceted roles of TRIM proteins in metabolic control and cell death, suggesting that ferroptosis may link TRIM proteins to lipid and amino acid metabolism, and highlights the connection between TRIM proteins and metabolic stress as a key area for future research.
    Keywords:  Cell death; Metabolic reprogramming; TRIM proteins; Therapeutic targets; Ubiquitination
    DOI:  https://doi.org/10.1016/j.metabol.2025.156394
  13. Nat Rev Drug Discov. 2025 Sep 23.
    Rebalancing cardiolipin biosynthesis to treat cardiomyopathy.
    Alex Eccleston.
      
    DOI:  https://doi.org/10.1038/d41573-025-00161-4
This page is being maintained by Thomas Krichel. It was last updated on 2025‒09‒28 at 2:23.