bims-lypmec 2023-04-30 papers

Arthritis Rheumatol. 2023 Apr 25.

LAMP3 induces lysosome-dependent cell death by impairing autophagic caspase-8 degradation in Sjögren's salivary glands.

Hiroyuki Nakamura, Tsutomu Tanaka, Changyu Zheng, Sandra A Afione, Blake M Warner, Masayuki Noguchi, Tatsuya Atsumi, John A Chiorini.

OBJECTIVE: Lysosome-associated membrane protein 3 (LAMP3) overexpression is implicated in the development and progression of Sjögren's disease (SjD) by inducing lysosomal membrane permeabilization (LMP) and apoptotic cell death in salivary gland epithelium. The aim of this study is to clarify molecular details of LAMP3-induced lysosome-dependent cell death and to test lysosomal biogenesis as a therapeutic intervention.
METHODS: Human labial minor salivary gland biopsies were immunofluorescently analyzed for LAMP3 expression levels and galectin-3 puncta formation, a marker of LMP. Expression level of caspase-8, an initiator of LMP, was determined by Western blotting in cell culture. Galectin-3 puncta formation and apoptosis were evaluated in cell culture and a mouse model treated with glucagon-like peptidase-1 receptor (GLP-1R) agonists, a known promoter of lysosomal biogenesis.
RESULTS: Galectin-3 puncta formation was more frequent in SjD patients' salivary glands compared to control glands. The proportion of galectin-3 puncta-positive cells was positively correlated with LAMP3 expression levels in the glands. LAMP3 overexpression increased caspase-8 expression, and knockdown of caspase-8 decreased galectin-3 puncta formation and apoptosis in LAMP3-overexpressing cells. Inhibition of autophagy increased caspase-8 expression, while restoration of lysosomal function using GLP-1R agonists decreased caspase-8 expression, which reduced galectin-3 puncta formation and apoptosis in both LAMP3-overexpressing cells and mice.
CONCLUSION: LAMP3 overexpression induced lysosomal dysfunction, resulting in lysosome-dependent cell death via impaired autophagic caspase-8 degradation, and restoring lysosomal function by GLP-1R agonists could prevent this. These findings suggested that LAMP3-induced lysosomal dysfunction is central to disease development and a target for therapeutic intervention in SjD. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/art.42540

Cell Rep. 2023 Apr 26. pii: S2211-1247(23)00446-1. [Epub ahead of print]42(5): 112435

Organelle interactions compartmentalize hepatic fatty acid trafficking and metabolism.

Charles P Najt, Santosh Adhikari, Timothy D Heden, Wenqi Cui, Erica R Gansemer, Adam J Rauckhorst, Todd W Markowski, LeeAnn Higgins, Evan W Kerr, Matthew D Boyum, Jonas Alvarez, Sophia Brunko, Dushyant Mehra, Elias M Puchner, Eric B Taylor, Douglas G Mashek.

Organelle interactions play a significant role in compartmentalizing metabolism and signaling. Lipid droplets (LDs) interact with numerous organelles, including mitochondria, which is largely assumed to facilitate lipid transfer and catabolism. However, quantitative proteomics of hepatic peridroplet mitochondria (PDM) and cytosolic mitochondria (CM) reveals that CM are enriched in proteins comprising various oxidative metabolism pathways, whereas PDM are enriched in proteins involved in lipid anabolism. Isotope tracing and super-resolution imaging confirms that fatty acids (FAs) are selectively trafficked to and oxidized in CM during fasting. In contrast, PDM facilitate FA esterification and LD expansion in nutrient-replete medium. Additionally, mitochondrion-associated membranes (MAM) around PDM and CM differ in their proteomes and ability to support distinct lipid metabolic pathways. We conclude that CM and CM-MAM support lipid catabolic pathways, whereas PDM and PDM-MAM allow hepatocytes to efficiently store excess lipids in LDs to prevent lipotoxicity.

Keywords: CP: Metabolism; MAM; cytosolic mitochondria; fatty acids; lipid anabolism; lipid catabolism; lipid droplets; organelle interactions; peridroplet mitochondria; perilipin 5; single-molecule localization microscopy

DOI: https://doi.org/10.1016/j.celrep.2023.112435

Nat Aging. 2023 Apr 17.

CISH impairs lysosomal function in activated T cells resulting in mitochondrial DNA release and inflammaging.

Jun Jin, Yunmei Mu, Huimin Zhang, Ines Sturmlechner, Chenyao Wang, Rohit R Jadhav, Qiong Xia, Cornelia M Weyand, Jorg J Goronzy.

Chronic systemic inflammation is one of the hallmarks of the aging immune system. Here we show that activated T cells from older adults contribute to inflammaging by releasing mitochondrial DNA (mtDNA) into their environment due to an increased expression of the cytokine-inducible SH2-containing protein (CISH). CISH targets ATP6V1A, an essential component of the proton pump V-ATPase, for proteasomal degradation, thereby impairing lysosomal function. Impaired lysosomal activity caused intracellular accumulation of multivesicular bodies and amphisomes and the export of their cargos, including mtDNA. CISH silencing in T cells from older adults restored lysosomal activity and prevented amphisomal release. In antigen-specific responses in vivo, CISH-deficient CD4+ T cells released less mtDNA and induced fewer inflammatory cytokines. Attenuating CISH expression may present a promising strategy to reduce inflammation in an immune response of older individuals.

DOI: https://doi.org/10.1038/s43587-023-00399-w