Abstract
Mitochondrial dysfunction and cell death play important roles in diabetic cardiomyopathy, but the underlying mechanisms remain unclear. Here, we report that mitochondrial dysfunction and cell apoptosis are prominent features of primary cardiomyocytes after exposure to high glucose/palmitate conditions. The protein level of MIC60, a core component of mitochondrial cristae, is decreased via ubiquitination and degradation under these conditions. Exogenous expression of MIC60 alleviates cristae disruption, mitochondrial dysfunction and apoptosis. Moreover, we identified MARCH5 as an E3 ubiquitin ligase that specifically targets MIC60 in this process. Indeed, MARCH5 mediates K48-linked ubiquitination of MIC60 at Lys285 to promote its degradation. Mutation of the ubiquitination site in MIC60 or the MIC60-interacting motifs in MARCH5 abrogates MARCH5-mediated MIC60 ubiquitination and degradation. Silencing MARCH5 significantly alleviates high glucose/palmitate-induced mitochondrial dysfunction and apoptosis in primary cardiomyocytes. In addition to E3 ubiquitin ligases, molecular chaperones also play important roles in protein stability. We previously reported that the mitochondrial chaperone TRAP1 inhibits the ubiquitination of MIC60, but the detailed mechanism is unknown. Here, we find that TRAP1 performs this function by competing with MARCH5 for binding to MIC60. Our findings provide new insights into the mechanism underlying mitochondrial dysfunction in cardiomyocytes in diabetic cardiomyopathy.
MARCH5 promotes ubiquitination of MIC60 to induce MIC60 degradation, mitochondrial dysfunction and apoptosis in cardiomyocytes under diabetic conditions. TRAP1 inhibits MARCH5-mediated ubiquitination by competitively interacting with MIC60.
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All the data used during the study are available from the corresponding author on request.
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Funding
This work were supported in part by the National Natural Science Foundation of China (Nos. 82270872, 82171604, 81971759 and 82300909), Natural Science Foundation of Guangdong (No. 2022A1515012249 and 2023B1515020108) and Science and Technology Planning Project of Guangzhou (No. 202206010089).
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LZ, GL, and TZ conceived of the project. LZ, SC, GL, TZ supervised the experiments, analyzed the data, and wrote the manuscript. LZ, YL, LL performed cellular and molecular experiments. All the authors discussed the results and commented on the manuscript.
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Zhang, L., Luo, Y., Lv, L. et al. TRAP1 inhibits MARCH5-mediated MIC60 degradation to alleviate mitochondrial dysfunction and apoptosis of cardiomyocytes under diabetic conditions. Cell Death Differ 30, 2336–2350 (2023). https://doi.org/10.1038/s41418-023-01218-w
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DOI: https://doi.org/10.1038/s41418-023-01218-w
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