bims-lypmec 2023-12-31 papers

Proc Natl Acad Sci U S A. 2024 Jan 02. 121(1): e2312306120

Lysophagy protects against propagation of α-synuclein aggregation through ruptured lysosomal vesicles.

Keita Kakuda, Kensuke Ikenaka, Akiko Kuma, Junko Doi, César Aguirre, Nan Wang, Takahiro Ajiki, Chi-Jing Choong, Yasuyoshi Kimura, Shaymaa Mohamed Mohamed Badawy, Takayuki Shima, Shuhei Nakamura, Kousuke Baba, Seiichi Nagano, Yoshitaka Nagai, Tamotsu Yoshimori, Hideki Mochizuki.

The neuron-to-neuron propagation of misfolded α-synuclein (αSyn) aggregates is thought to be key to the pathogenesis of synucleinopathies. Recent studies have shown that extracellular αSyn aggregates taken up by the endosomal-lysosomal system can rupture the lysosomal vesicular membrane; however, it remains unclear whether lysosomal rupture leads to the transmission of αSyn aggregation. Here, we applied cell-based αSyn propagation models to show that ruptured lysosomes are the pathway through which exogenous αSyn aggregates transmit aggregation, and furthermore, this process was prevented by lysophagy, i.e., selective autophagy of damaged lysosomes. αSyn aggregates accumulated predominantly in lysosomes, causing their rupture, and seeded the aggregation of endogenous αSyn, initially around damaged lysosomes. Exogenous αSyn aggregates induced the accumulation of LC3 on lysosomes. This LC3 accumulation was not observed in cells in which a key regulator of autophagy, RB1CC1/FIP200, was knocked out and was confirmed as lysophagy by transmission electron microscopy. Importantly, RB1CC1/FIP200-deficient cells treated with αSyn aggregates had increased numbers of ruptured lysosomes and enhanced propagation of αSyn aggregation. Furthermore, various types of lysosomal damage induced using lysosomotropic reagents, depletion of lysosomal enzymes, or more toxic species of αSyn fibrils also exacerbated the propagation of αSyn aggregation, and impaired lysophagy and lysosomal membrane damage synergistically enhanced propagation. These results indicate that lysophagy prevents exogenous αSyn aggregates from escaping the endosomal-lysosomal system and transmitting aggregation to endogenous cytosolic αSyn via ruptured lysosomal vesicles. Our findings suggest that the progression and severity of synucleinopathies are associated with damage to lysosomal membranes and impaired lysophagy.

Keywords: lysophagy; lysosomal vesicle rupture; synucleinopathy; α-synuclein

DOI: https://doi.org/10.1073/pnas.2312306120

Am J Physiol Cell Physiol. 2023 Dec 25.

Cholesterol Trafficking, Lysosomal Function and Atherosclerosis.

Alaa Skeyni, Alain Pradignac, Rachel L Matz, Jerome Terrand, Phillippe Boucher.

Despite years of study and major research advances over the past 50 years, atherosclerotic diseases continue to rank as the leading global cause of death. Accumulation of cholesterol within the vascular wall remained the main problem and represented one of the early steps in the development of atherosclerotic lesions. There is a complex relationship between vesicular cholesterol transport and atherosclerosis, and abnormalities in cholesterol trafficking can contribute to the development and progression of the lesions. The dysregulation of vesicular cholesterol transport and lysosomal function fosters the buildup of cholesterol within various intracytoplasmic compartments, including lysosomes and lipid droplets. This, in turn, promotes the hallmark formation of foam cells, a defining feature of early atherosclerosis. Multiple cellular processes, encompassing endocytosis, exocytosis, intracellular trafficking, and autophagy, play crucial roles in influencing foam cell formation and atherosclerotic plaque stability. In this review, we will highlight recent advances in the understanding of the intricate mechanisms of vesicular cholesterol transport and its relationship with atherosclerosis, and will discuss the importance of understanding these mechanisms in developing strategies to prevent or treat this prevalent cardiovascular disease.

Keywords: Lysosome; autophagy; interorganellar communications; mTORC1; metabolism

DOI: https://doi.org/10.1152/ajpcell.00415.2023

J Cell Sci. 2023 Dec 15. pii: jcs261413. [Epub ahead of print]136(24):

Dipping contacts - a novel type of contact site at the interface between membraneless organelles and membranes.

Christian Hoffmann, Dragomir Milovanovic.

Liquid-liquid phase separation is a major mechanism for organizing macromolecules, particularly proteins with intrinsically disordered regions, in compartments not limited by a membrane or a scaffold. The cell can therefore be perceived as a complex emulsion containing many of these membraneless organelles, also referred to as biomolecular condensates, together with numerous membrane-bound organelles. It is currently unclear how such a complex concoction operates to allow for intracellular trafficking, signaling and metabolic processes to occur with high spatiotemporal precision. Based on experimental observations of synaptic vesicle condensates - a membraneless organelle that is in fact packed with membranes - we present here the framework of dipping contacts: a novel type of contact site between membraneless organelles and membranes. In this Hypothesis, we propose that our framework of dipping contacts can serve as a foundation to investigate the interface that couples the diffusion and material properties of condensates to biochemical processes occurring in membranes. The identity and regulation of this interface is especially critical in the case of neurodegenerative diseases, where aberrant inclusions of misfolded proteins and damaged organelles underlie cellular pathology.

Keywords: Dipping contacts; Liquid–liquid phase separation; Membranes; Neurodegenerative diseases; Synapse

DOI: https://doi.org/10.1242/jcs.261413

JACC Asia. 2023 Dec;3(6): 908-921

Association of Metabolic Dysfunction-Associated Fatty Liver Disease With Risk of HF and AF.

Ryusei Ohno, Hidehiro Kaneko, Yuta Suzuki, Akira Okada, Satoshi Matsuoka, Kensuke Ueno, Katsuhito Fujiu, Nobuaki Michihata, Taisuke Jo, Norifumi Takeda, Hiroyuki Morita, Koichi Node, Hideo Yasunaga, Issei Komuro.

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a novel concept of hepatic disease. Although the prevalences of heart failure (HF) and atrial fibrillation (AF) are increasing worldwide, limited data have assessed the extent to which MAFLD is associated with incident HF and AF.
Objectives: The authors sought to examine the association of MAFLD with incident HF and AF.
Methods: Analyses were conducted using a nationwide epidemiologic database including 3,279,918 individuals (median age 45 years; 57.6% men). Metabolic dysfunction was defined as 1 or more of the following: overweight (body mass index ≥23 kg/m2), metabolic syndrome, or diabetes mellitus. FLD was defined as fatty liver index of >30. MAFLD was defined as the coexistence of metabolic dysfunction and FLD. We categorized study participants into 4 groups: non-FLD/nonmetabolic dysfunction (n = 1,709,116), metabolic dysfunction (n = 584,483), FLD (n = 89,497), and MAFLD (n = 896,822). The primary outcomes were HF and AF.
Results: Over a mean follow-up period of 1,160 ± 905 days, 62,746 incident HF events and 15,408 incident AF events were recorded. Compared with the non-FLD/non-metabolic dysfunction group, HRs for HF and AF, respectively, were 1.20 (95% CI: 1.18-1.23) and 1.13 (95% CI: 1.08-1.19) for metabolic dysfunction, 1.24 (95% CI: 1.19-1.30) and 1.13 (95% CI: 1.04-1.23) for FLD, and 1.73 (95% CI: 1.69-1.76) and 1.51 (95% CI: 1.46-1.57) for MAFLD. MAFLD was also associated with a higher risk of developing myocardial infarction, angina pectoris, and stroke. A risk of developing cardiovascular events differed between MAFLD subtypes (Wald test P < 0.001).
Conclusions: MAFLD was associated with a greater risk of developing HF and AF, suggesting the clinical importance of this novel hepatic disease concept.

Keywords: atrial fibrillation; epidemiology; heart failure; metabolic dysfunction–associated fatty liver disease

DOI: https://doi.org/10.1016/j.jacasi.2023.08.003