bims-lypmec 2025-05-25 papers

Autophagy Rep. 2024 ;3(1): 2412916

Getting PIKy with the lysosome membrane (again).

Much is still unknown about microautophagy and its regulators. In our recent paper, one such regulator of microautophagy, the lipid kinase PIKfyve, is described. Previously it was found that treating cells with agents like lysomotropic drugs or proton ionophores, which alter lysosomal osmotic potential and pH, leads to a form of microautophagy that selectively degrades transmembrane proteins. Induction of this type of microautophagy is linked to a lysosomal stress response that involves the targeting of macroautophagy proteins, like ATG8s, to the lysosome membrane, through a mechanism called CASM. We found that CASM-induced microautophagy turns over ATG8s and other lysosomal membrane proteins, and requires PIKfyve activity functioning downstream of ATG8 lipidation. The lysosome biogenesis transcription factor TFEB is induced in parallel to microautophagy, in a CASM-dependent, but PIKfyve-independent manner. These findings demonstrate that stressors that engage CASM cause selective turnover by microautophagy that is coordinated with lysosome biogenesis through a mechanism that is separable through PIKfyve.

Keywords: ATG8; CASM; LC3; PIKfyve; TFEB; TRPML1; autophagy; lysosome; microautophagy

DOI: https://doi.org/10.1080/27694127.2024.2412916

Autophagy Rep. 2025 ;4(1): 2498324

Amino acid storage: lysosomal double role in health and disease.

Aiswarya Raj, Samantha Shrihari, Urmi Bandyopadhyay.

Cellular homeostasis depends on a multitude of cellular functions, which in turn depend on the clearance of damaged components for their maintenance. Lysosomes being one of the main sites of recycling, are at the frontline for cellular protein degradation, which leads to generation of protein building blocks, the amino acids (AAs), within the lysosomal lumen. However, the fate of these lysosomal pool of AAs are only partly known. Recently, studies from our and other groups have led to the finding that AA can be stored in lysosomes and revealed a homeostatic communication of these storages with the environment. Thus, lysosome appear to be a nutritional signaling hub that has a dual role. As a degradation-competent hydrolytic sack, lysosomes have a long-studied degradative function, additionally now they can either store or channel into utilization of the AAs generated through their proteolytic activity. Since the existence of a lysosomal AA storage pool has been determined by changing the levels of extracellular AAs, this indicates a multi-directional homeostatic communication between the lysosome and the extracellular environment. This Lysosomal homeostatic and adaptive response to the niche could be vital for life-threatening age-related degenerative disorders, where the lysosome-autophagy pathway and the microenvironmental cues play major roles in the disease progression, which will be discussed further in this piece.

Keywords: Extracellular Environment; LAMTOR-RAG GTPase complex; Lysosome; leucine; nutrient storage

DOI: https://doi.org/10.1080/27694127.2025.2498324

Autophagy Rep. 2024 ;3(1): 2320605

Crosstalk between myocardial autophagy and sterile inflammation in the development of heart failure.

Jialing Tang, Eddie Tam, Erfei Song, Aimin Xu, Gary Sweeney.

Heart failure, a leading driver of global mortality, remains a topic of intense contemporary research interest due to the prevailing unmet need in cardiometabolic therapeutics. Numerous mechanisms with the potential to influence the onset and development of heart failure remain incompletely understood. Firstly, myocardial autophagy, which involves lysosomal degradation of damaged cellular components, confers context-dependent beneficial and detrimental effects. Secondly, sterile inflammation may arise following cardiac stress and exacerbate the progression of heart failure. Inflammation changes in a temporal manner and its onset must be adequately resolved to limit progression of heart failure. Mitochondria are an important factor in contributing to sterile inflammation by releasing damage associated molecular patterns (DAMPs) including mitochondrial DNA (mtDNA). Accordingly, this is one reason why the selective autophagy of mitochondria to maintain optimal function is important in determining cardiac function. In this review, we examine the increasing evidence suggesting crosstalk between autophagy and sterile inflammation together with their role in the development of heart failure. In particular, this is exemplified in the preclinical models of ischaemia/reperfusion injury and pressure overload induced heart failure. We also highlight potential therapeutic approaches focusing on autophagy and addressing sterile inflammation, aiming to enhance outcomes in heart failure.

Keywords: Autophagy; heart failure; ischaemia/reperfusion; pressure overload; sterile inflammation

DOI: https://doi.org/10.1080/27694127.2024.2320605

Bioorg Chem. 2025 May 12. pii: S0045-2068(25)00465-1. [Epub ahead of print]162 108585

Lysosome-specific fluorescent probe for malondialdehyde/formaldehyde detection in oxidative/carbonyl stressed nerve cells and foods.

Xueting Liu, Zilu Li, Ziyi Wang, Kun Wang, Xiaodi Rong, Yao Wang, Tingyi Yan, Wei Shu, Caiyun Liu, Baocun Zhu.

Research on neurodegenerative diseases has become a significant area of study. Oxidative/carbonyl stress are fundamental pathophysiological mechanisms in neurodegenerative diseases, and their processes are strongly associated with malondialdehyde (MDA) and formaldehyde (FA). There is a complex interaction between oxidative/carbonyl stress and lysosomal dysfunction, which together are involved in the pathological processes of neurodegenerative diseases. And lysosome targeted detection can intuitively reflect the degree of lysosome damage. Therefore, understanding the complex interplay between oxidative/carbonyl stress, lysosomal dysfunction, and the formation of MDA/FA is essential for elucidating the pathological processes involved. In addition, the determination of MDA/FA is also necessary to ensure food safety. Thus, we synthesized a naphthalimide-based fluorescent probe with aminoethyl morpholine as the lysosomal targeting site and hydrazine group as the recognition site. In the recognition processes, the probe reacts with MDA/FA to form different chemical groups, enabling it to differentiate and identify MDA/FA. The probe has good sensitivity and anti-interference ability. The fluorescence imaging of MDA/FA within lysosomes of nerve cells was accomplished for the first time. Additionally, we observed an increase in MDA/FA concentrations under oxidative/carbonyl stress, providing a valuable basis for understanding their relationship in neurodegenerative diseases. Furthermore, the application of this probe to various food samples demonstrates its potential as a forceful tool for food safety detection. To summarize, this study provides a new scientific basis for diagnosis of neurodegenerative diseases, and offers a robust means for ensuring food safety.

Keywords: Fluorescence probe; Food samples; Formaldehyde; Lysosome-targeted; Malondialdehyde; Oxidative stress

DOI: https://doi.org/10.1016/j.bioorg.2025.108585

Autophagy Rep. 2024 ;3(1): 2409563

Truncated tau disrupts autophagy and endolysosomal systems.

Saskia J Pollack, Diane P Hanger, Wendy Noble, Maria Jimenez-Sanchez.

Keywords: Alzheimer’s disease; TFEB; Tau; autophagy; dementia; endosomes; lysosomes; tauopathies

DOI: https://doi.org/10.1080/27694127.2024.2409563