Abstract
Lysosomal dysfunction has been found in many pathological conditions, and methods to improve lysosomal function have been reported to be protective against infarcted hearts. However, the mechanisms underlying lysosomal dysfunction caused by ischemic injury are far less well-established. The retromer complex is implicated in the trafficking of cation-independent mannose 6-phosphate receptor (CI-MPR), which is an important protein tag for the proper transport of lysosomal contents and therefore is important for the maintenance of lysosomal function. In this study, we found that the function of retrograde transport in cardiomyocytes was impaired with ischemia/hypoxia (I/H) treatment, which resulted in a decrease in CI-MPR and an abnormal distribution of lysosomal cathepsins. I/H treatment caused a reduction in TBC1D5 and a blockade of the Rab7 membrane cycle, which impeded retromer binding to microtubules and motor proteins, resulting in an impairment of retrograde transport and a decrease in CI-MPR. We also established that TBC1D5 was an important regulator of the distribution of lysosomal cathepsins. Our findings shed light on the regulatory role of retromer in ischemic injury and uncover the regulatory mechanism of TBC1D5 over retromer.
Highlights
Cardiac ischemic/hypoxic injuries exist in many pathological conditions, including myocardial infarction, severe burns [1] and traumatic hemorrhage [2, 3], but the underlying mechanisms are still under mist
Previous studies have reported that myocardial infarction causes a decrease in the activities of lysosomal hydrolases accompanied by elevated activities in the serum, which contributes to heart dysfunction [12, 13]
The protein level of Cation-independent mannose 6-phosphate receptor (CIMPR) presented a time-dependent decrease (Figures 1A,B), and cation-dependent mannose 6-phosphate receptor (CD-MPR) showed similar changes (Figures 1C,D). These results suggested that I/H treatment impeded the trafficking of cathepsin B and cathepsin D, which probably contributed to the dysfunction of lysosomes
Summary
Cardiac ischemic/hypoxic injuries exist in many pathological conditions, including myocardial infarction, severe burns [1] and traumatic hemorrhage [2, 3], but the underlying mechanisms are still under mist. Recent discoveries have uncovered their critical role as signal transduction platforms, regulators of cellular energy metabolism and cell death control These functions of lysosomes interactively and cooperatively regulate cellular homeostasis [4,5,6]. Lysosomal dysfunction, represented by the decreased degradation capacities of lysosomal hydrolases, is found in various pathological conditions, including lysosomal storage disorders [7, 8], Retromer Dysfunction in I/H Cardiomyocytes neurodegenerative diseases [9,10,11] and cardiac ischemic injuries [12, 13]. Therapeutic strategies targeting improving the activities of lysosomal hydrolases have been reported to ameliorate pathological damage [9, 12, 13]
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