VDAC2 malonylation participates in sepsis-induced myocardial dysfunction via mitochondrial-related ferroptosis

Abstract

Sepsis-induced myocardial dysfunction (SIMD) is a prevalent and severe form of organ dysfunction with elusive underlying mechanisms and limited treatment options. In this study, the cecal ligation and puncture and lipopolysaccharide (LPS) were used to reproduce sepsis model in vitro and vivo. The level of voltage-dependent anion channel 2 (VDAC2) malonylation and myocardial malonyl-CoA were detected by mass spectrometry and LC-MS-based metabolomics. Role of VDAC2 malonylation on cardiomyocytes ferroptosis and treatment effect of mitochondrial targeting nano material TPP-AAV were observed. The results showed that VDAC2 lysine malonylation was significantly elevated after sepsis. In addition, the regulation of VDAC2 lysine 46 (K46) malonylation by K46E and K46Q mutation affected mitochondrial-related ferroptosis and myocardial injury. The molecular dynamic simulation and circular dichroism further demonstrated that VDAC2 malonylation altered the N-terminus structure of the VDAC2 channel, causing mitochondrial dysfunction, increasing mitochondrial ROS levels, and leading to ferroptosis. Malonyl-CoA was identified as the primary inducer of VDAC2 malonylation. Furthermore, the inhibition of malonyl-CoA using ND-630 or ACC2 knock-down significantly reduced the malonylation of VDAC2, decreased the occurrence of ferroptosis in cardiomyocytes, and alleviated SIMD. The study also found that the inhibition of VDAC2 malonylation by synthesizing mitochondria targeting nano material TPP-AAV could further alleviate ferroptosis and myocardial dysfunction following sepsis. In summary, our findings indicated that VDAC2 malonylation plays a crucial role in SIMD and that targeting VDAC2 malonylation could be a potential treatment strategy for SIMD.

TRIM8 promotes ovarian cancer proliferation and migration by targeting VDAC2 for ubiquitination and degradation

“…45 Malonylation of VDAC2 may induce mitochondrial dysfunction, increase mitochondrial ROS levels, lead to cell iron death, and inhibit tumor development. 46 The present study found that VDAC2 knockdown increased the resistance of cells to erastin-induced iron death, suggesting that VDAC2 silencing could indeed increase cell resistance to iron death, therebt promoting tumor development. In addition, rescue experiments showed that VDAC2 could reduce the cancer-promoting effect induced by TRIM8.…”

“…In addition, VDAC2 activation plays a key role in iron death, and knockdown of VDAC2 can increase cell resistance to iron death 45 . Malonylation of VDAC2 may induce mitochondrial dysfunction, increase mitochondrial ROS levels, lead to cell iron death, and inhibit tumor development 46 . The present study found that VDAC2 knockdown increased the resistance of cells to erastin‐induced iron death, suggesting that VDAC2 silencing could indeed increase cell resistance to iron death, therebt promoting tumor development.…”

Mechanistic engineering of celastrol liposomes induces ferroptosis and apoptosis by directly targeting VDAC2 in hepatocellular carcinoma

“…4 D). Previous studies have shown that VDAC2 is involved in the regulation of mitochondria-related ferroptosis, mitochondrial ROS level and BAX-mediated apoptosis for limiting tumor development [46] , [47] . These could be well matched with the biological processes and functions of VDAC2, suggesting that Cel binding to VDAC2 induces ferroptosis and apoptosis in hepatic cancer cells.…”

Development of macrophage-associated genes prognostic signature predicts clinical outcome and immune infiltration for sepsis

“…Sepsis represents a critical global health challenge, contributing significantly to the worldwide burden of morbidity and mortality. The Global Burden of Disease Study reports that in 2020, sepsis accounted for approximately 48.9 million incidences and 11 million fatalities across the globe 1 . Factors such as a burgeoning elderly population, the escalation of chronic disease prevalence, and a surge in antibiotic resistance have been implicated in the rising incidence of sepsis 2 .…”