bims-lypmec 2023-05-14 papers

FEBS J. 2023 May 11.

Characterization of the role of TMEM175 in an in vitro lysosomal H+ fluxes model.

Chuanyan Yang, Fuyun Tian, Mei Hu, Chunlan Kang, Meixuan Ping, Yiyao Liu, Meiqin Hu, Haoxing Xu, Ye Yu, Zhaobing Gao, Ping Li.

Lysosome acidification is a dynamic equilibrium of H+ influx and efflux across the membrane, which is crucial for cell physiology. The vacuolar H+ ATPase (V-ATPase) is responsible for the H+ influx or refilling of lysosomes. TMEM175 was identified as a novel H+ permeable channel on lysosomal membranes, and it plays a critical role in lysosome acidification. However, how TMEM175 participates in lysosomal acidification remains unknown. Here, we present evidence that TMEM175 regulates lysosomal H+ influx and efflux in enlarged lysosomes isolated from COS1 treated with vacuolin-1. By utilizing the whole-endolysosome patch-clamp recording technique, a series of integrated lysosomal H+ influx and efflux signals in a ten-of-second time scale under the physiological pH gradient (luminal pH 4.60, and cytosolic pH 7.20) was recorded from this in vitro system. Lysosomal H+ fluxes constitute both the lysosomal H+ refilling and releasing, and they are asymmetrical processes with distinct featured kinetics for each of the H+ fluxes. Lysosomal H+ fluxes are entirely abolished when TMEM175 losses of function in the F39V mutant and is blocked by the antagonist (2-GBI). Meanwhile, lysosomal H+ fluxes are modulated by the pH-buffering capacity of the lumen and the lysosomal glycosylated membrane proteins, lysosome-associated membrane protein 1 (LAMP1). We propose that the TMEM175-mediated lysosomal H+ fluxes model would provide novel thoughts for studying the pathology of Parkinson`s disease and lysosome storage disorders.

Keywords: H+ leak; TMEM175; glycocalyx; lysosome acidification; proton channel

DOI: https://doi.org/10.1111/febs.16814

Nat Commun. 2023 May 08. 14(1): 2654

Lysosomal-associated protein transmembrane 5 ameliorates non-alcoholic steatohepatitis by promoting the degradation of CDC42 in mice.

Lang Jiang, Jing Zhao, Qin Yang, Mei Li, Hao Liu, Xiaoyue Xiao, Song Tian, Sha Hu, Zhen Liu, Peiwen Yang, Manhua Chen, Ping Ye, Jiahong Xia.

Non-alcoholic steatohepatitis (NASH) has received great attention due to its high incidence. Here, we show that lysosomal-associated protein transmembrane 5 (LAPTM5) is associated with NASH progression through extensive bioinformatical analysis. The protein level of LAPTM5 bears a negative correlation with NAS score. Moreover, LAPTM5 degradation is mediated through its ubiquitination modification by the E3 ubquitin ligase NEDD4L. Discovered by experiments conducted on male mice, hepatocyte-specific depletion of Laptm5 exacerbates mouse NASH symptoms. In contrast, Laptm5 overexpression in hepatocytes exerts diametrically opposite effects. Mechanistically, LAPTM5 interacts with CDC42 and promotes its degradation through a lysosome-dependent manner under the stimulation of palmitic acid, thus inhibiting activation of the mitogen-activated protein kinase signaling pathway. Finally, adenovirus-mediated hepatic Laptm5 overexpression ameliorates aforementioned symptoms in NASH models.

DOI: https://doi.org/10.1038/s41467-023-37908-9

J Biol Chem. 2023 May 05. pii: S0021-9258(23)01816-1. [Epub ahead of print] 104788

Adverse cardiac remodeling augments adipose tissue ß-adrenergic signaling and lipolysis counteracting diet-induced obesity.

Stephanie Kolleritsch, Laura Pajed, Anna Tilp, Victoria Hois, Isabella Potoschnig, Benedikt Kien, Clemens Diwoky, Gerald Hoefler, Gabriele Schoiswohl, Guenter Haemmerle.

Cardiac triacylglycerol (TAG) accumulation is a common characteristic of obesity and type 2 diabetes and strongly correlates with heart morbidity and mortality. We have previously shown that cardiomyocyte-specific Perilipin 5 overexpression (Plin5-Tg) provokes significant cardiac steatosis via lowering cardiac lipolysis and fatty acid (FA) oxidation. In strong contrast to cardiac steatosis and lethal heart dysfunction in Adipose triglyceride lipase deficiency, Plin5-Tg mice do not develop heart dysfunction and show a normal life span on chow diet. This finding prompted us to study heart function and energy metabolism in Plin5-Tg mice fed high-fat diet (HFD). Plin5-Tg mice showed adverse cardiac remodeling on HFD with heart function only being compromised in one-year-old mice, likely due to reduced cardiac FA uptake, thereby delaying deleterious cardiac lipotoxicity. Notably, Plin5-Tg mice were less obese and protected from glucose intolerance on HFD. Changes in cardiac energy catabolism in Plin5-Tg mice increased ß-adrenergic signaling, lipolytic and thermogenic protein expression in adipose tissue ultimately counteracting HFD-induced obesity. Acute cold exposure further augmented ß-adrenergic signaling in Plin5-Tg mice, whereas housing at thermoneutrality did not protect Plin5-Tg mice from HFD-induced obesity albeit blood glucose and insulin levels remained low in transgenic mice. Overall, our data suggest that the limited capacity for myocardial FA oxidation on HFD increases cardiac stress in Plin5-Tg mice, thereby stimulating adipose tissue ß-adrenergic signaling, TAG catabolism, and thermogenesis. However, long-term HFD-mediated metabolic stress causes contractile dysfunction in Plin5-Tg mice, which emphasizes the importance of a carefully controlled dietary regime in patients with cardiac steatosis and hypertrophy.

Keywords: Perilipin 5; adipose tissue; cardiac hypertrophy; lipolysis; thermogenesis

DOI: https://doi.org/10.1016/j.jbc.2023.104788

Front Endocrinol (Lausanne). 2023 ;14 1140644

Ferroptosis: roles and molecular mechanisms in diabetic cardiomyopathy.

Yangting Zhao, Binjing Pan, Xiaoyu Lv, Chongyang Chen, Kai Li, Yawen Wang, Jingfang Liu.

Diabetic cardiomyopathy (DCM) is a serious complication of type 1 and type 2 diabetes, which leads to the aggravation of myocardial fibrosis, disorders involving systolic and diastolic functions, and increased mortality of patients with diabetes through mechanisms such as glycolipid toxicity, inflammatory response, and oxidative stress. Ferroptosis is a form of iron-dependent regulatory cell death that is attributed to the accumulation of lipid peroxides and an imbalance in redox regulation. Increased production of lipid reactive oxygen species (ROS) during ferroptosis promotes oxidative stress and damages myocardial cells, leading to myocardial systolic and diastolic dysfunction. Overproduction of ROS is an important bridge between ferroptosis and DCM, and ferroptosis inhibitors may provide new targets for the treatment of patients with DCM.

Keywords: diabetes mellitus; diabetic cardiomyopathy; ferroptosis; iron metabolism; oxidative stress

DOI: https://doi.org/10.3389/fendo.2023.1140644