bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2026–08–09
six papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Organelle contact sites as spatial regulators of lipid fate in adipose tissue metabolic disease.
  2. Exercise-induced lysosomal adaptations in skeletal muscle.
  3. Lysosomal metabolism in pancreatic cancer and its crosstalk with host physiology.
  4. Calpain-2 inhibition prevents pressure overload-induced lysosomal cathepsin release and cardiac hypertrophy.
  5. ATP6AP2 ameliorates inflammation and pyroptosis in heart failure by promoting lysosome-dependent STING degradation.
  6. Cardiomyocyte OTUD7b drives diabetic cardiomyopathy via deubiquitinating and stabilizing TAK1.
  1. Life Sci. 2026 Aug 07. pii: S0024-3205(26)00433-9. [Epub ahead of print] 124624
    Organelle contact sites as spatial regulators of lipid fate in adipose tissue metabolic disease.
    Yiqin Yan, Lupeng Chen.
      Adipose tissue protects metabolic homeostasis by storing excess fatty acids, releasing fuels during energy demand and coordinating endocrine and inflammatory signals. These functions are often described as linear pathways of lipogenesis, lipolysis, fatty acid oxidation and thermogenesis. However, lipid handling in adipocytes is spatially organized by organelle contact sites. The endoplasmic reticulum (ER), lipid droplets (LDs), mitochondria, peroxisomes and lysosomes form dynamic interfaces that determine whether fatty acids are stored safely, mobilized for oxidation, processed into specialized lipid species or redirected toward lipotoxic intermediates. In this review, we synthesize evidence that ER-LD and LD-mitochondria contacts coordinate lipid storage and oxidative use, whereas peroxisome-centred contacts connect lipolysis, very-long-chain and branched-chain fatty acid processing, plasmalogen metabolism and mitochondrial remodelling. We further discuss how autophagy and lysosomal pathways maintain adipocyte quality control by regulating LD turnover, mitophagy and membrane renewal. Finally, we propose that obesity, insulin resistance, ectopic lipid deposition, lipodystrophy and adipose inflammation can be viewed as different manifestations of impaired spatial lipid routing. This framework does not replace classical metabolic models, but provides a mechanistic layer that may help identify contact-site-dependent vulnerabilities in metabolic disease.
    Keywords:  Adipose tissue; Lipid droplets; Lipophagy; Metabolic disease; Mitochondria; Organelle contact sites; Peroxisomes
    DOI:  https://doi.org/10.1016/j.lfs.2026.124624
  2. Sports Med Health Sci. 2026 Sep;8(5): 487-494
    Exercise-induced lysosomal adaptations in skeletal muscle.
    Anastasiya Kuznyetsova, David A Hood.
      The adoption of a regular exercise program has immense benefits for whole body health, and for improving the quality of skeletal muscle. This is important as muscle is involved in metabolism, locomotion, and force production, making it a large contributor to the quality of life. The coordinated behavior of several intracellular organelles is responsible for the maintenance of skeletal muscle health, and these organelles are adaptable in response to both acute and chronic exercise. While the adaptations of mitochondria to exercise are well-established, potential alterations in muscle lysosomes are less appreciated. Lysosomes degrade and recycle debris during the terminal step of various forms of autophagy, such as mitophagy, the pathway involved in the removal of dysfunctional mitochondria. This lysosomal activity is important for the maintenance of cellular protein and organelle homeostasis. Recent work has shown that lysosome biogenesis begins with every acute bout of exercise, driven by the nuclear translocation of regulatory transcription factors such as TFEB and TFE3, which mediate the transcription of autophagy and lysosomal genes. These transcription factors also play a role in other pathways such as chaperone-mediated autophagy (CMA) and the regeneration of existing lysosomes through the autophagic-lysosome reformation (ALR) pathway. When performed repeatedly, acute bouts of exercise elicit a longer-term adaptive response, leading to the formation of active lysosomes, which increase lysosomal degradative capacity in skeletal muscle. This review addresses the current knowledge surrounding the effects of acute and chronic exercise on lysosomal adaptations in skeletal muscle, highlighting a novel pathway of muscle plasticity.
    Keywords:  Autophagic lysosome reformation; Chaperone-mediated autophagy (CMA); Exercise training; Macroautophagy; Mitophagy; Skeletal muscle; TFEB; Transcriptional regulation
    DOI:  https://doi.org/10.1016/j.smhs.2026.06.001
  3. Genes Dev. 2026 Aug 06.
    Lysosomal metabolism in pancreatic cancer and its crosstalk with host physiology.
    Caleb Cheng, Rüya Pakkan, Arul M Chinnaiyan, Costas A Lyssiotis.
      Pancreatic ductal adenocarcinoma (PDAC) grows within a highly fibrotic, pressurized microenvironment that collapses vasculature and restricts delivery of oxygen and circulating nutrients. To survive this metabolic stress, PDAC cells activate lysosome-centered nutrient acquisition and recycling programs, including macroautophagy, RAS-driven macropinocytosis, and receptor-mediated endocytosis, that traffic intracellular and extracellular cargo to lysosomes for degradation and metabolite export. These pathways are reinforced by oncogenic signaling and MiT/TFE-dependent lysosomal biogenesis, and they support core outputs of tumor metabolism such as iron bioavailability, amino acid and nucleotide pools, lipid homeostasis, and immune evasion. Lysosomal programs in nonmalignant compartments (fibroblasts, stellate cells, and immune cells) further shape nutrient exchange, matrix production, and whole-body metabolism, positioning the lysosome as a key node at the tumor-host interface. Although genetic and pharmacologic blockade of autophagy/lysosome function can produce potent antitumor effects in preclinical models, clinical trials with lysosomotropic agents have shown limited benefit, highlighting challenges in target engagement, biomarkers, and rational combination strategies. Here we review current tools and concepts for interrogating lysosomal flux in PDAC, integrate emerging insights from systemic metabolism and dietary interventions, and outline therapeutic opportunities for more effectively exploiting lysosome dependence in pancreatic cancer.
    Keywords:  lysosome metabolism; pancreatic cancer; tumor host metabolism
    DOI:  https://doi.org/10.1101/gad.353702.126
  4. Life Sci. 2026 Aug 07. pii: S0024-3205(26)00423-6. [Epub ahead of print] 124614
    Calpain-2 inhibition prevents pressure overload-induced lysosomal cathepsin release and cardiac hypertrophy.
    Anna Martí-Boltaina, David Aluja, Sara Delgado-Tomás, Elisabet Miró-Casas, Rafael Rodriguez-Lecoq, Marisol Ruiz-Meana, Antonio Rodriguez-Sinovas, Begoña Benito, Elena Garcia-Trevijano, Elena Gutierrez-Calabres, Michel Baudry, José A Barrabés, Ignacio Ferreira-González, Javier Inserte.
       AIMS: Dysregulated calpains and cathepsins contribute to adverse cardiac remodeling following chronic pathological stress, but their interplay and the specific contributions of the classical calpain isoforms remain undefined. Here, we tested whether calpain-2 initiates a lysosome-cathepsin proteolytic axis that promotes pathological hypertrophy through mTORC1-dependent signaling.
    MATERIALS AND METHODS: Calpain expression was analyzed in septal myocardium from patients with aortic stenosis and mice subjected to transverse aortic constriction (TAC). Calpain activity was modulated genetically by Capns1 deletion or pharmacologically with the calpain-2 inhibitor NA-184 in TAC mice. Cathepsins were inhibited with balicatib. In vitro, Capn2 was silenced by siRNA in H9c2 cardiomyoblasts stimulated with angiotensin II.
    KEY FINDINGS: TAC upregulated myocardial calpain-2 expression, which correlated with hypertrophy severity in septal tissue from patients. TAC induced lysosomal membrane permeabilization, evidenced by reduced cathepsin B-lysosome colocalization, and increased cytosolic cathepsin accumulation and activity. Mechanistically, calpain-2 cleaved the lysosomal protein LAMP2, generating a ~ 55 kDa fragment. Both Capns1 deletion and NA-184 preserved LAMP2 and lysosomal integrity, reduced autophagic dysregulation and the activation of the AKT/mTOR signaling, and attenuated cardiac hypertrophy. Capn2 silencing in H9c2 reproduced the effects by reducing LAMP2 proteolysis and hypertrophy. Balicatib produced comparable anti-hypertrophic effects, supporting a sequential calpain-cathepsin signaling cascade. When treatment was extended, NA-184 limited ventricular dilation and attenuated systolic dysfunction (30%, p < 0.001).
    SIGNIFICANCE: These findings identify calpain-2-mediated LAMP2 proteolysis as an upstream trigger linking lysosomal dysfunction to pathological hypertrophy, and highlight selective calpain-2 inhibition as a therapeutic strategy for heart failure treatment.
    Keywords:  Calpains; Cathepsins; Heart failure; Hypertrophy
    DOI:  https://doi.org/10.1016/j.lfs.2026.124614
  5. Apoptosis. 2026 Aug 02. pii: 202. [Epub ahead of print]31(8):
    ATP6AP2 ameliorates inflammation and pyroptosis in heart failure by promoting lysosome-dependent STING degradation.
    Xuan Zhao, Hui Zhang, Xinyue Ding, Huimin Wu, Min Li, Nengpin Yin, Junqing Gao, Youlong Xu, Rui Wang, Zhen Qi, Lina Xing, Zongjun Liu.
      Inflammatory activation is involved in the pathogenesis of heart failure (HF). ATPase H+-Transporting Accessory Protein 2 (ATP6AP2) is an auxiliary subunit of the V-ATPase, and its role in HF is not fully understood. To assess the role and regulatory mechanisms and therapeutic potential of ATP6AP2 in HF, we used a cardiac-specific ATP6AP2 conditional knockout (CKO) mouse model and observed spontaneous cardiac dysfunction, myocardial fibrosis and cardiomyocyte apoptosis in mice. Further studies showed that ATP6AP2 promoted stimulator of interferon genes (STING) degradation through the lysosome-dependent pathway. ATP6AP2 knockdown significantly upregulated STING protein levels, activated the STING-TBK1-IRF3 signaling axis, and promoted pro-inflammatory factor expression and cardiomyocyte apoptosis. In mice with myocardial infarction (MI), myocardial overexpression of ATP6AP2 or treatment with H-151 inhibited the activation of the STING signaling pathway, ameliorated cardiomyocyte apoptosis and inflammatory responses, thereby improving cardiac function. In addition, in macrophages treated with conditioned medium from hypoxia-exposed cardiomyocytes, the levels of pyroptosis-related proteins were markedly increased, whereas ATP6AP2 overexpression or STING inhibition reduced pyroptosis. ATP6AP2 likewise attenuates inflammation and pyroptosis caused by hypoxia in cardiac organoids. In conclusion, activating ATP6AP2 could serve as a promising therapeutic option in HF.
    Keywords:  ATP6AP2; Heart failure; Inflammation; Lysosomes; STING
    DOI:  https://doi.org/10.1007/s10495-026-02415-x
  6. Acta Pharmacol Sin. 2026 Aug 03.
    Cardiomyocyte OTUD7b drives diabetic cardiomyopathy via deubiquitinating and stabilizing TAK1.
    Xue Han, Guo-Xuan Liu, Jia-Ning Zheng, Ming-Yang He, Li Zhuang, Jia-Jia Zhang, Jie Tong, Zhu-Qi Huang, Yu-Rou Wu, Tong-Qing Zhou, Ju-Lin Min, Ze-Ping Zhang, Ning Zhu, Qiao-Juan Shi, Wen-Bing Jiang, Hua-Zhong Ying, Guang Liang.
      Deubiquitinating enzymes (DUBs) are critically involved in diabetic cardiomyopathy (DCM), yet the function of OTU domain-containing protein 7B (OTUD7b), a recently identified DUB, in DCM remains unknown. Here, we identified that OTUD7b expression was significantly elevated in cardiomyocytes from both type 1 and type 2 diabetic mouse hearts. Cardiomyocyte-specific deletion of OTUD7b ameliorated cardiac dysfunction, hypertrophy, and fibrosis in diabetic mice, without affecting systemic hyperglycemia. Mechanistically, combining ubiquitinome and interactome analyses, we identified transforming growth factor β-activated kinase 1 (TAK1) as a direct substrate of OTUD7b in cardiomyocytes. Under diabetic conditions, OTUD7b binds to TAK1 via its zinc finger domain and catalyzes K48-linked deubiquitination at the K346 of TAK1, thereby enhancing TAK1 protein stability. This OTUD7b-mediated stabilization increased the levels of both TAK1 and p-TAK1, which led to hyperactivation of the TAK1-MAPK (JNK/p38) axis, subsequently promoting extrinsic apoptosis and inflammatory responses in cardiomyocytes. Crucially, cardiomyocyte-specific reconstitution of a deubiquitination-resistant TAK1-K346R mutant in diabetic mice completely abolished the cardioprotective effects of OTUD7b deficiency, confirming that OTUD7b drives DCM primarily through deubiquitinating TAK1 at K346. Taken together, our study unveils a novel OTUD7b-TAK1 axis in cardiomyocytes driving diabetic heart injury and positions OTUD7b as a promising therapeutic target for DCM.
    Keywords:  OTUD7b; TAK1; apoptosis; deubiquitinating enzyme; diabetic cardiomyopathy; inflammation
    DOI:  https://doi.org/10.1038/s41401-026-01891-w
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