bims-lypmec 2025-06-29 papers

bims-lypmec

Biomed News

on Lysosomal positioning and metabolism in cardiomyocytes

Issue of 2025–06–29
ten papers selected by
Satoru Kobayashi, New York Institute of Technology

Rag GTPases control lysosomal acidification by regulating v-ATPase assembly in Drosophila.
Inhibition of lysosomal LAMTOR1 increases autophagy by suppressing the MTORC1 pathway to ameliorate lipid accumulations in MAFLD.
A lysosomal surveillance response to stress extends healthspan.
Naringenin and SMER28 target lysosomal reformation and rescue SPG11 and SPG15 hereditary spastic paraplegia phenotypes.
Emerging Concepts of Targeted Protein Degrader Technologies via Lysosomal Pathways.
Key challenges and recommendations for defining organelle membrane contact sites.
Diabetic cardiomyopathy revisited: The interplay between diabetes and heart failure.
Acidosis attenuates the hypoxic stabilization of HIF-1α by activating lysosomal degradation.
NAD+ repletion restores cardioprotective autophagy and mitophagy in obesity-associated heart failure by suppressing excessive trophic signaling.
Cardiac intermediary metabolism in heart failure: substrate use, signalling roles and therapeutic targets.

J Biol Chem. 2025 Jun 19. pii: S0021-9258(25)02250-1. [Epub ahead of print] 110400

Rag GTPases control lysosomal acidification by regulating v-ATPase assembly in Drosophila.

Ying Zhou, Xiaodie Yang, Wenyu Xu, Sulin Shen, Weikang Fan, Guoqiang Meng, Yang Cheng, Yingying Lu, Youheng Wei.

  The Rag GTPases play an important role in sensing amino acids and activating the target of rapamycin complex 1 (TORC1), a master regulator of cell metabolism. Previously, we have shown that GDP-bound RagA stimulates lysosome acidification and autophagic degradation, which are essential for young egg chamber survival under starvation in Drosophila. However, the underlying mechanism is unclear. Here we demonstrate that the GDP-bound RagA breaks the physical interaction between chaperonin containing tailless complex polypeptide 1 (CCT) and Vacuolar H+-ATPase (v-ATPase) subunit V1, and thus promotes the assembly of active v-ATPase and increases the lysosomal acidification. Consistently, knockdown of CCT complex components rescued the accumulation of defective autolysosomes in RagA RNAi. Moreover, the knockdown of Lamtor4, a component of lysosomal adaptor and MAPK and mTOR activator (LAMTOR) that anchors Rag GTPases to the lysosome, resulted in autolysosome accumulation, suggesting that RagGTPases regulate lysosomal acidification depend on their lysosomal localization. Knockdown of the CCT complex components attenuated the autophagic defects in Lamtor 4 RNAi. Our work highlights the interaction between CCT and v-ATPase in regulating lysosomal acidification.

Keywords:  Drosophila melanogaster; Rag GTPases; V-ATPase assembly; autophagy; chaperonin containing tailless complex polypeptide 1

DOI:  https://doi.org/10.1016/j.jbc.2025.110400
Autophagy. 2025 Jun 23.

Inhibition of lysosomal LAMTOR1 increases autophagy by suppressing the MTORC1 pathway to ameliorate lipid accumulations in MAFLD.

Yunyeong Jang, Minjeong Ko, Ju Yeon Lee, Jin Young Kim, Eun-Woo Lee, Ho Jeong Kwon.

  Metabolic dysfunction-associated fatty liver disease (MAFLD) is a serious metabolic disorder characterized by fat accumulation in the liver, which can trigger liver inflammation and fibrosis, potentially leading to cirrhosis or liver cancer. Despite many studies, effective treatments for MAFLD remain elusive due to its complex etiology. In this study, we have focused on the discovery of therapeutic agents and molecular targets for MAFLD treatment. We demonstrated that the natural compound acacetin (ACA) alleviates MAFLD by regulating macroautophagy/autophagy in a CDAHFD mouse model of rapidly induced steatohepatitis. In addition, ACA inhibits lipid accumulation in 3T3-L1 adipocytes through autophagy induction. To identify the target responsible for the autophagy activity induced by ACA, we performed drug affinity responsive target stability (DARTS) combined with LC-MS/MS proteomic analysis. This led to the identification of LAMTOR1 (late endosomal/lysosomal adaptor, MAPK and MTOR activator 1), a lysosomal membrane adaptor protein. We found that binding of ACA to LAMTOR1 induces its release from the LAMTOR complex, leading to inhibition of MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1), thereby increasing autophagy. This process helps ameliorate metabolic disorders by modulating the MTORC1-AMPK axis. Genetic knockdown of LAMTOR1 phenocopies the effects of ACA treatment, further supporting the role of LAMTOR1 as a target of ACA. These findings suggest LAMTOR1 plays a crucial role in ACA's therapeutic effects on MAFLD. In summary, our study identifies LAMTOR1 as a key protein target of ACA, revealing a potential therapeutic avenue for MAFLD by modulating autophagy via the LAMTOR1-MTORC1-AMPK signaling pathway.

Keywords:  Acacetin; DARTS; LAMTOR1; MAFLD; MTORC1; autophagy

DOI:  https://doi.org/10.1080/15548627.2025.2519054
Nat Cell Biol. 2025 Jun 26.

A lysosomal surveillance response to stress extends healthspan.

Terytty Yang Li, Arwen W Gao, Rendan Yang, Yu Sun, Yuxuan Lei, Xiaoxu Li, Lin Chen, Yasmine J Liu, Rachel N Arey, Kimberly Morales, Raya B Liu, Wenzheng Wang, Ang Zhou, Tong-Jin Zhao, Weisha Li, Amélia Lalou, Qi Wang, Tanes Lima, Riekelt H Houtkooper, Johan Auwerx.

Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H+-ATPase subunits (for example, vha-6), which are essential for intestinal lumen acidification in Caenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive transcriptional response typified by induction of a set of transcripts involved in lysosomal function and proteolysis, which we termed the lysosomal surveillance response (LySR). LySR activation is characterized by boosted lysosomal activity and enhanced clearance of protein aggregates in worm models of Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis, thereby improving fitness. The GATA transcription factor ELT-2 governs the LySR programme and its associated beneficial effects. Activating the LySR pathway may therefore represent an attractive mechanism to reduce proteotoxicity and, as such, potentially extend healthspan.

DOI: https://doi.org/10.1038/s41556-025-01693-y
Pharmacol Res. 2025 Jun 21. pii: S1043-6618(25)00261-0. [Epub ahead of print]218 107836

Naringenin and SMER28 target lysosomal reformation and rescue SPG11 and SPG15 hereditary spastic paraplegia phenotypes.

Chiara Vantaggiato, Giulia Guarato, Francesca Brivio, Elena Panzeri, Beatrice Speltoni, Sentiljana Gumeni, Genny Orso, Filippo Maria Santorelli, Maria Teresa Bassi.

  SPG11 and SPG15 are two hereditary spastic paraplegia forms characterized by autophagosome accumulation, reduced free lysosomes and defects in autophagic lysosomal reformation (ALR). We demonstrated that attempts to rescue ALR and/or lysosome biogenesis are critical strategies for SPG15 phenotype and that SMER28 improved lysosomal reformation rescuing locomotor deficit in a SPG15 Drosophila model. Here we assessed the therapeutic potential of two FDA-approved compounds, tideglusib and naringenin, that target lysosomal function and regeneration, both registered for clinical use. Their effects were compared with those of SMER28 and of miglustat, the latter tested in a phase II clinical trial in SPG11 patients, in both SPG15 and SPG11 patient's derived cells and in the corresponding Drosophila models. We demonstrated that naringenin and SMER28 restored lysosomal and autophagic parameters in SPG15 and SPG11 cells and fly models, rescued ALR and improved locomotor deficit in vivo. Both compounds induced lysosomal tubulation, downstream of mTOR, promoting lysosomal reformation. Our work indicates that lysosomal reformation is a good strategy for herditary spastic parapegia forms with impaired lysosomal function and identifies naringenin as new modulator of this process, offering further hand to planning phase II clinical trials in SPG11-SPG15 patients.

Keywords:  ALR; Lysosomes; Naringenin; SMER28; SPG11; SPG15; Tideglusib

DOI:  https://doi.org/10.1016/j.phrs.2025.107836
Int J Mol Sci. 2025 Jun 11. pii: 5582. [Epub ahead of print]26(12):

Emerging Concepts of Targeted Protein Degrader Technologies via Lysosomal Pathways.

Mohammad Maqusood Alam, Sobia Wasim, Sang-Yoon Lee.

  Targeted protein degradation (TPD) has emerged as a revolutionary strategy for modulating protein function, offering a promising alternative to traditional small-molecule inhibitors. The distinctive mechanism of action in TPD has previously allowed researchers to target undruggable proteins, broadening the scope of "druggable" properties and expanding the scope of therapeutic possibilities. As the field of TPD advances, several alternative strategies to proteolysis-targeting chimeras (PROTACs) have emerged, which do not rely on the E3 ubiquitin ligase recruitment mechanism, expending the scope of TPD. Recently, several new technologies have emerged for TPD of extracellular and membrane proteins. While encouraging progress has been made in this field, the application of these technologies remains in its early stages. In this review, we explore the therapeutic potential of current key emerging lysosome-mediated TPD approaches by summarizing key discoveries and address the challenges associated with degrading extracellular and membrane protein targets. We also outline the chemical structure, activity, and pharmaceutical properties of each degrader, as well as the development of chemical probes for perturbing autophagy pathways.

Keywords:  autophagy receptor; bifunctional antibody; extracellular protein; lysosomal degradation; membrane protein; target protein degrader (TPD)

DOI:  https://doi.org/10.3390/ijms26125582
Nat Rev Mol Cell Biol. 2025 Jun 23.

Key challenges and recommendations for defining organelle membrane contact sites.

Tito Calì, Emmanuelle M Bayer, Emily R Eden, György Hajnóczky, Benoit Kornmann, Laura Lackner, Jen Liou, Karin Reinisch, Hyun-Woo Rhee, Rosario Rizzuto, Luca Scorrano, Marisa Brini.

Intracellular membrane contact sites (MCSs) between organelles have crucial roles in cellular signalling and homeostasis. These sites, which are often disrupted in pathological conditions, enable the exchange of ions, lipids and metabolites between membrane-bound compartments, helping cells adapt to varying physiological conditions. Specific tether proteins and complexes stabilize these interactions and mediate responses to different intracellular or extracellular stimuli. The study of MCSs has progressed in recent years, owing to the development of new methods such as genetically encoded reporter constructs, advanced imaging techniques, including super-resolution microscopy and electron tomography, and proteomic approaches based on mass spectrometry. These tools have enabled unprecedented visualization and quantification of organelle interactions, as well as identification of the molecular players involved. This Expert Recommendation aims to define and map the 'organelle contactome', describing key proteins involved in contact site formation and the roles of MCSs in cellular function. We also explore contact site dynamics and detail advantages and disadvantages of the methodologies for studying them. Importantly, we consolidate open questions in contact site research and discuss challenges and limitations of the current experimental approaches.

DOI: https://doi.org/10.1038/s41580-025-00864-x
Int J Cardiol. 2025 Jun 24. pii: S0167-5273(25)00597-2. [Epub ahead of print] 133554

Diabetic cardiomyopathy revisited: The interplay between diabetes and heart failure.

Christopher Mann, Eugene Braunwald, Thomas A Zelniker.

  Diabetic cardiomyopathy is a complex condition characterized by structural and functional changes in the heart, which are not explained by other known cardiovascular risk factors in patients with diabetes. Since Rubler first described this condition in 1972, there has been significant progress in understanding the multifactorial mechanisms that contribute to the development and progression of heart failure in diabetic patients. In this review, we provide a comprehensive discussion of the key mechanisms that underlie the development of diabetic cardiomyopathy, including chronic hyperglycemia, autonomic neuropathy, altered substrate utilization, and dysregulated insulin pathways. We also compare the distinct characteristics of heart failure in type 1 and type 2 diabetes and review the effects of antidiabetic medications on heart failure in diabetic patients with a particular emphasis on ongoing clinical trials.

Keywords:  Diabetic cardiomyopathy; Heart failure; Hyperglycemia; Insulin resistance; Myocardial metabolism; SGLT2 inhibitors

DOI:  https://doi.org/10.1016/j.ijcard.2025.133554
J Cell Biol. 2025 Aug 04. pii: e202409103. [Epub ahead of print]224(8):

Acidosis attenuates the hypoxic stabilization of HIF-1α by activating lysosomal degradation.

Bobby White, Zhenyi Wang, Matthew Dean, Johanna Michl, Natalia Nieora, Sarah Flannery, Iolanda Vendrell, Roman Fischer, Alzbeta Hulikova, Pawel Swietach.

Hypoxia-inducible factors (HIFs) mediate cellular responses to low oxygen, notably enhanced fermentation that acidifies poorly perfused tissues and may eventually become more damaging than adaptive. How pH feeds back on hypoxic signaling is unclear but critical to investigate because acidosis and hypoxia are mechanistically coupled in diffusion-limited settings, such as tumors. Here, we examined the pH sensitivity of hypoxic signaling in colorectal cancer cells that can survive acidosis. HIF-1α stabilization under acidotic hypoxia was transient, declining over 48 h. Proteomic analyses identified responses that followed HIF-1α, including canonical HIF targets (e.g., CA9, PDK1), but these did not reflect a proteome-wide downregulation. Enrichment analyses suggested a role for lysosomal degradation. Indeed, HIF-1α destabilization was blocked by inactivating lysosomes, but not proteasome inhibitors. Acidotic hypoxia stimulated lysosomal activity and autophagy via mammalian target of rapamycin complex I (mTORC1), resulting in HIF-1α degradation. This response protects cells from excessive acidification by unchecked fermentation. Thus, alkaline conditions are permissive for at least some aspects of HIF-1α signaling.

DOI: https://doi.org/10.1083/jcb.202409103
Autophagy. 2025 Jun 24.

NAD+ repletion restores cardioprotective autophagy and mitophagy in obesity-associated heart failure by suppressing excessive trophic signaling.

Mahmoud Abdellatif, Francisco Vasques-Nóvoa, João Pedro Ferreira, Junichi Sadoshima, Abhinav Diwan, Wolfgang A Linke, Guido Kroemer, Simon Sedej.

  Macroautophagy/autophagy is markedly inhibited in the hearts of elderly obese patients with heart failure and preserved ejection fraction (HFpEF). However, the therapeutic relevance and underlying signaling mechanisms of the decline of autophagy in HFpEF remain unclear. We observed that therapeutic nicotinamide adenine dinucleotide (NAD+) repletion via nicotinamide supplementation restores cardioprotective autophagy and mitophagy in preclinical models of obesity-related HFpEF. Targeted and untargeted cardiac acetylome profiling revealed no significant deacetylation of essential autophagy-related proteins, including ATG5, ATG7 and mammalian Atg8-family members (ATG8s), suggesting a SIRT (sirtuin)-independent mechanism of autophagy induction by nicotinamide. Instead, cardiac transcriptomic analysis revealed major shifts in insulin-IGF1 (insulin-like growth factor 1) signaling, a known autophagy inhibitory pathway. Nicotinamide supplementation reversed the HFpEF-associated increase in insulin-IGF1 signaling, whereas exogenous IGF1 counteracts nicotinamide-induced autophagy. Importantly, nicotinamide fails to exert cardioprotective effects in mice lacking the autophagy-related protein ATG5 in cardiomyocytes, implicating autophagy as essential for the therapeutic response. In patients with HFpEF, a metabolic shift diverting nicotinamide away from NAD+ biosynthesis toward catabolism strongly correlates with worsening heart failure and increased cardiovascular mortality, even after adjusting for traditional risk factors. In sum, we demonstrate that NAD+ replenishment improves cardiometabolic HFpEF by restoring cardiac autophagy through suppression of excessive IGF1 signaling.

Keywords:  Acetylation; HFpEF; IGF1; insulin; nutrient signaling; sirtuins

DOI:  https://doi.org/10.1080/15548627.2025.2522127
Nat Rev Cardiol. 2025 Jun 22.

Cardiac intermediary metabolism in heart failure: substrate use, signalling roles and therapeutic targets.

Mathias Mericskay, Coert J Zuurbier, Lisa C Heather, Anja Karlstaedt, Javier Inserte, Luc Bertrand, Georgios Kararigas, Marisol Ruiz-Meana, Christoph Maack, Gabriele G Schiattarella.

The number of patients with heart failure is expected to rise sharply owing to ageing populations, poor dietary habits, unhealthy lifestyles and improved survival rates from conditions such as hypertension and myocardial infarction. Heart failure is classified into two main types: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). These forms fundamentally differ, especially in how metabolism is regulated, but they also have shared features such as mitochondrial dysfunction. HFrEF is typically driven by neuroendocrine activation and mechanical strain, which demands a higher ATP production to sustain cardiac contraction. However, the primary energy source in a healthy heart (fatty acid β-oxidation) is often suppressed in HFrEF. Although glucose uptake increases in HFrEF, mitochondrial dysfunction disrupts glucose oxidation, and glycolysis and ketone oxidation only partially compensate for this imbalance. Conversely, HFpEF, particularly in individuals with metabolic diseases, such as obesity or type 2 diabetes mellitus, results from both mechanical and metabolic overload. Elevated glucose and lipid levels overwhelm normal metabolic pathways, leading to an accumulation of harmful metabolic byproducts that impair mitochondrial and cellular function. In this Review, we explore how disruptions in cardiac metabolism are not only markers of heart failure but also key drivers of disease progression. We also examine how metabolic intermediates influence signalling pathways that modify proteins and regulate gene expression in the heart. The growing recognition of the role of metabolic alterations in heart failure has led to groundbreaking treatments that target these metabolic disruptions, offering new hope for these patients.

DOI: https://doi.org/10.1038/s41569-025-01166-7