bims-lypmec 2023-04-16 papers

Issue of 2023‒04‒16
five papers selected by
Satoru Kobayashi
New York Institute of Technology

J Cell Biol. 2023 Jun 05. pii: e202210063. [Epub ahead of print]222(6):

Lysosomal chloride transporter CLH-6 protects lysosome membrane integrity via cathepsin activation.

Qianqian Zhang, Yuan Li, Youli Jian, Meijiao Li, Xiaochen Wang.

Lysosomal integrity is vital for cell homeostasis, but the underlying mechanisms are poorly understood. Here, we identify CLH-6, the C. elegans ortholog of the lysosomal Cl-/H+ antiporter ClC-7, as an important factor for protecting lysosomal integrity. Loss of CLH-6 affects lysosomal degradation, causing cargo accumulation and membrane rupture. Reducing cargo delivery or increasing CPL-1/cathepsin L or CPR-2/cathepsin B expression suppresses these lysosomal defects. Inactivation of CPL-1 or CPR-2, like CLH-6 inactivation, affects cargo digestion and causes lysosomal membrane rupture. Thus, loss of CLH-6 impairs cargo degradation, leading to membrane damage of lysosomes. In clh-6(lf) mutants, lysosomes are acidified as in wild type but contain lower chloride levels, and cathepsin B and L activities are significantly reduced. Cl- binds to CPL-1 and CPR-2 in vitro, and Cl- supplementation increases lysosomal cathepsin B and L activities. Altogether, these findings suggest that CLH-6 maintains the luminal chloride levels required for cathepsin activity, thus facilitating substrate digestion to protect lysosomal membrane integrity.

DOI: https://doi.org/10.1083/jcb.202210063

Cell Death Dis. 2023 04 08. 14(4): 255

Cathepsin B in programmed cell death machinery: mechanisms of execution and regulatory pathways.

Zhen Xie, Mengyuan Zhao, Chengxiang Yan, Wei Kong, Fei Lan, Narengaowa, Shuxuan Zhao, Qinghu Yang, Zhantao Bai, Hong Qing, Junjun Ni.

Cathepsin B (CatB), a cysteine protease, is primarily localized within subcellular endosomal and lysosomal compartments. It is involved in the turnover of intracellular and extracellular proteins. Interest is growing in CatB due to its diverse roles in physiological and pathological processes. In functional defective tissues, programmed cell death (PCD) is one of the regulable fundamental mechanisms mediated by CatB, including apoptosis, pyroptosis, ferroptosis, necroptosis, and autophagic cell death. However, CatB-mediated PCD is responsible for disease progression under pathological conditions. In this review, we provide an overview of the critical roles and regulatory pathways of CatB in different types of PCD, and discuss the possibility of CatB as an attractive target in multiple diseases. We also summarize current gaps in the understanding of the involvement of CatB in PCD to highlight future avenues for research.

DOI: https://doi.org/10.1038/s41419-023-05786-0

Circ Res. 2023 Apr 14. 132(8): 1034-1049

Cardiac Metabolism in Heart Failure and Implications for Uremic Cardiomyopathy.

T Dung Nguyen, P Christian Schulze.

Chronic kidney disease is associated with an increased risk for the development and progression of cardiovascular disorders including hypertension, dyslipidemia, and coronary artery disease. Chronic kidney disease may also affect the myocardium through complex systemic changes, resulting in structural remodeling such as hypertrophy and fibrosis, as well as impairments in both diastolic and systolic function. These cardiac changes in the setting of chronic kidney disease define a specific cardiomyopathic phenotype known as uremic cardiomyopathy. Cardiac function is tightly linked to its metabolism, and research over the past 3 decades has revealed significant metabolic remodeling in the myocardium during the development of heart failure. Because the concept of uremic cardiomyopathy has only been recognized in recent years, there are limited data on metabolism in the uremic heart. Nonetheless, recent findings suggest overlapping mechanisms with heart failure. This work reviews key features of metabolic remodeling in the failing heart in the general population and extends this to patients with chronic kidney disease. The knowledge of similarities and differences in cardiac metabolism between heart failure and uremic cardiomyopathy may help identify new targets for mechanistic and therapeutic research on uremic cardiomyopathy.

Keywords: heart failure; metabolism; renal insufficiency, chronic

DOI: https://doi.org/10.1161/CIRCRESAHA.123.321759

Cardiovasc Res. 2023 Apr 11. pii: cvad052. [Epub ahead of print]

Microtubule plus-end tracking proteins: novel modulators of cardiac sodium channels and arrhythmogenesis.

Gerard A Marchal, Niels Galjart, Vincent Portero, Carol Ann Remme.

The cardiac sodium channel NaV1.5 is an essential modulator of cardiac excitability, with decreased NaV1.5 levels at the plasma membrane and consequent reduction in sodium current (INa) leading to potentially lethal cardiac arrhythmias. NaV1.5 is distributed in a specific pattern at the plasma membrane of cardiomyocytes, with localization at the crests, grooves, and T-tubules of the lateral membrane, and particularly high levels at the intercalated disc region. NaV1.5 forms a large macromolecular complex with and is regulated by interacting proteins, some of which are specifically localised at either the lateral membrane or intercalated disc. One of the NaV1.5 trafficking routes is via microtubules (MTs), which are regulated by MT plus-end tracking proteins (+TIPs). In our search for mechanisms involved in targeted delivery of NaV1.5, we here provide an overview of previously demonstrated interactions between NaV1.5 interacting proteins and +TIPs, which potentially (in)directly impact on NaV1.5 trafficking. Strikingly, +TIPs interact extensively with several intercalated disc- and lateral membrane-specific NaV1.5 interacting proteins. Recent work indicates that this interplay of +TIPs and NaV1.5 interacting proteins mediates the targeted delivery of NaV1.5 at specific cardiomyocyte subcellular domains, while also being potentially relevant for the trafficking of other ion channels. These observations are especially relevant for diseases associated with loss of NaV1.5 specifically at the lateral membrane (such as Duchenne muscular dystrophy), or at the intercalated disc (for example, arrhythmogenic cardiomyopathy), and open up potential avenues for development of new anti-arrhythmic therapies.

DOI: https://doi.org/10.1093/cvr/cvad052