bims-lypmec 2024-04-28 papers

Chembiochem. 2024 Apr 25. e202400232

Lysosomal Peptide Self-Assembly To Control Cell Behavior.

Lysosomes are membrane-enclosed organelles that play key roles in degrading and recycling cellular debris, cellular signaling, and energy metabolism processes. Confinement of amphiphilic peptides in the lysosome to construct functional nanostructures through noncovalent interactions is an emerging approach to tune the homeostasis of lysosome. After briefly introducing the importance of lysosome and its functions, we discuss the advantages of lysosomal nanostructure formation for disease therapy. We next discuss the strategy for triggering the self-assembly of peptides in the lysosome, followed by a concise outlook of the future perspective about this emerging research direction.

Keywords: Cancer therapy; Lysosome; Peptide; nanofibers; self-assembly

DOI: https://doi.org/10.1002/cbic.202400232

Biosci Rep. 2024 Apr 24. pii: BSR20231992. [Epub ahead of print]

Cardiomyocyte-specific deletion of the mitochondrial transporter Abcb10 causes cardiac dysfunction via lysosomal-mediated ferroptosis.

Yura Do, Mikako Yagi, Haruka Hirai, Kenji Miki, Yukina Fikahori, Daiki Setoyama, Masatatsu Yamamoto, Tatsuhiko Furukawa, Yuya Kunishaki, Dongchon Kang, Takeshi Uchiumi.

Heart function is highly dependent on mitochondria, which not only produce energy but also regulate many cellular functions. Therefore, mitochondria are important therapeutic targets in heart failure. Abcb10 is a member of the ABC transporter superfamily located in the inner mitochondrial membrane and plays an important role in haemoglobin synthesis, biliverdin transport, antioxidant stress, and stabilization of the iron transporter mitoferrin-1. However, the mechanisms underlying the impairment of mitochondrial transporters in the heart remain poorly understood. Here we generated mice with cardiomyocyte-specific loss of Abcb10. The Abcb10 knockouts exhibited progressive worsening of cardiac fibrosis, increased cardiovascular risk markers and mitochondrial structural abnormalities, suggesting that the pathology of heart failure is related to mitochondrial dysfunction. As the mitochondrial dysfunction was observed early but mildly, other factors were considered. We then observed increased Hif1α expression, decreased NAD synthase expression, and reduced NAD+ levels, leading to lysosomal dysfunction. Analysis of ABCB10 knockdown HeLa cells revealed accumulation of Fe2+ and lipid peroxides in lysosomes, leading to ferroptosis. Lipid peroxidation was suppressed by treatment with iron chelators, suggesting that lysosomal iron accumulation is involved in ferroptosis. We also observed that Abcb10 knockout cardiomyocytes exhibited increased ROS production, iron accumulation, and lysosomal hypertrophy. Our findings suggest that Abcb10 is required for the maintenance of cardiac function and reveal a novel pathophysiology of chronic heart failure related to lysosomal function and ferroptosis.

Keywords: heart failure; lysosomes; mitochondria

DOI: https://doi.org/10.1042/BSR20231992

Mol Biol Rep. 2024 Apr 26. 51(1): 579

Unravelling the role of cathepsins in cardiovascular diseases.

Sonali Maheshwari, Bhoomika M Patel.

Lysosomal cathepsins as a regulatory medium have been assessed as potential therapeutic targets for the treatment of various cardiac diseases such as abdominal aortic aneurysm, hypertension, cardiomyopathy, coronary heart disease, atherosclerosis, etc. They are ubiquitous lysosomal proteases with papain-like folded protein structures that are involved in a variety of physiological processes, such as the digestion of proteins, activation of pro-inflammatory molecules, degradation of extracellular matrix components, and maturation of peptide hormones. Cathepsins are classified into three major groups: cysteine cathepsins, aspartic cathepsins, and serine-threonine cathepsins. Each of these groups is further divided into subgroups based on their substrate specificity, structural characteristics, and biochemical properties. Several studies suggest that cathepsins control the degradation of ECM components such as collagen and elastin fibres. These enzymes are highly expressed in macrophages and inflammatory cells, and their upregulation has been demonstrated to be critical in the progression of atherosclerotic lesions. Additionally, increased cathepsin activity has been linked to increased vascular inflammation and oxidative stress, both of which are associated with CVDs. Specifically, the inhibition of cathepsins may reduce the release of pro-apoptotic mediators such as caspase-3 and PARP-1, which are thought to contribute to plaque instability. The potential of cathepsins as biomarkers and therapeutic targets has also been supported by the identification of potential cathepsin inhibitors, which could be used to modulate the activities of cathepsins in a range of diseases. This review shall familiarise the readers with the role of cysteinyl cathepsins and their inhibitors in the pathogenesis of cardiovascular diseases.

Keywords: Abdominal aortic aneurysm; Atherosclerosis; CVDs; Cardiovascular diseases; Cathepsins; Hypertension; Lysosomal proteases

DOI: https://doi.org/10.1007/s11033-024-09518-1

RSC Adv. 2024 Apr 16. 14(18): 12864-12872

Rational design of a lysosome-targeted fluorescent probe for monitoring the generation of hydroxyl radicals in ferroptosis pathways.

Lili Zhong, Datian Fu, Jin Xu, Linyan Tan, Haimei Wu, Min Wang.

Ferroptosis is a newly discovered iron-dependent form of regulated cell death associated with high levels of hydroxyl radical (˙OH) production. Meanwhile, lysosome dysfunction has been shown to be one of the causes of ferroptosis. Although a variety of ˙OH-responsive fluorescent probes have been developed for detecting intracellular ˙OH in living cells, there are still only few lysosome-targeted probes to monitor the variation in lysosomal ˙OH levels during ferroptosis. Herein, we report a novel ˙OH-specific fluorescent probe HCy-Lyso, which is composed of the hydrocyanine and morpholine moiety. Upon treatment with ˙OH, its hydrocyanine unit was converted to the corresponding cyanine group, thus leading to a large π-conjugation extension of HCy-Lyso, accompanied by a significant fluorescence off-on response. Moreover, after reacting with ˙OH in an acidic environment, the protonation product of HCy-Lyso exhibits a higher fluorescence enhancement, which is suitable for detecting lysosomal ˙OH variation. HCy-Lyso has been utilized for imaging endogenous ˙OH in living cells under phorbol myristate acetate (PMA) stimuli and monitoring the changes in lysosomal ˙OH levels during ferroptosis. Thus, our study proposes a new strategy to design lysosome-targeted and ˙OH-responsive fluorescent probes to investigate the relationship between lysosomes and ferroptosis.

DOI: https://doi.org/10.1039/d4ra00562g