The Lysosomal Membrane Protein Lamp2 Alleviates Lysosomal Cell Death by Promoting Autophagic Flux in Ischemic Cardiomyocytes

Abstract

Lysosomal membrane permeabilization (LMP) has recently been recognized as an important cell death pathway in various cell types. However, studies regarding the correlation between LMP and cardiomyocyte death are scarce. Lysosomal membraneassociated protein 2 (Lamp2) is an important component of lysosomal membranes and is involved in both autophagy and LMP. In the present study, we found that the protein content of Lamp2 gradually decreased in response to oxygen, glucose and serum deprivation (OGD) treatment in vitro. To further elucidate its role in ischemic cardiomyocytes, particularly with respect to autophagy and LMP, we infected cardiomyocytes with adenovirus carrying full-length Lamp2 to restore its protein level in cells. We found that OGD treatment resulted in the occurrence of LMP and a decline in the viability of cardiomyocytes, which were remarkably reversed by Lamp2 restoration. Exogenous expression of Lamp2 also significantly alleviated the autophagic flux blockade induced by OGD treatment by promoting the trafficking of cathepsin B (Cat B) and cathepsin D (Cat D). Through drug intervention and gene regulation to alleviate and exacerbate autophagic flux blockade respectively, we found that impaired autophagic flux in response to ischemic injury contributed to the occurrence of LMP in cardiomyocytes. In conclusion, our present data suggest that Lamp2 overexpression can improve autophagic flux blockade probably by promoting the trafficking of cathepsins and consequently conferring cardiomyocyte resistance against lysosomal cell death (LCD) that is induced by ischemic injury. These results may indicate a new therapeutic target for ischemic heart damage.

α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes

“…Interestingly, our results show that lysosomes containing α-syn fibrils are not targeted for lysophagy [84] (S4 Fig), possibly suggesting a rescue mechanism such as the one orchestrated by the endosomal sorting complexes required for transport (ESCRT) machinery [111,112]. Considering the evidence supporting autophagy impairment in NDs and more specifically following α-syn accumulation [55,113], and the recent findings that impaired autophagic flux contributes to the occurrence of LMP [114], it will be interesting to assess the contribution of autophagy to LMP, lysosomal dysfunction, and propagation of α-syn.…”

The Role of Autophagy in Skeletal Muscle Diseases

“…Ample evidence indicates that deficiency of LAMP-2 causes mistargeting of certain lysosomal enzymes and impaired capacity for lysosomal degradation ( Tanaka et al, 2000 ; Eskelinen et al, 2002 ), leading to disrupted phagosomal maturation, autophagosome-lysosome fusion, and accumulation of autophagosomes and resulting in myopathy and cardiomyopathy ( Tanaka et al, 2000 ; Saftig et al, 2008 ). In contrast, overexpression of Lamp2 can alleviate autophagic flux blockade likely due to stimulation of cathepsin trafficking, which may improve cardiomyocyte resistance to lysosomal cell death ( Cui et al, 2020 ).…”

Qianliexin capsule exerts anti‐inflammatory activity in chronic non‐bacterial prostatitis and benign prostatic hyperplasia via NF‐κB and inflammasome

“…QLX also reversed CGN‐induced decreased Atg4B in prostate (Figure 9D). Moreover, the lysosomal membrane protein LAMP2 was reported to potentiate autophagic flux in brain 32 and heart 33 . LAMP2 expression levels were therefore quantified by IF and Western blot.…”