Abstract
ObjectiveMitochondrial thioredoxin 2 (Trx2) is a vital mitochondrial redox protein that mediates normal protein thiol reduction and provides electrons to peroxiredoxin 3 (Prx3) to scavenge H2O2 in mitochondria. It has been widely reported that Trx2 deletion in cells or mice generates massive reactive oxygen species (ROS) which have been implicated in many pathological processes. On the contrary, how ROS regulate Trx2 processing and activity remains to be elucidated.Approach and ResultsHere we show that excess ROS induce endothelial cell senescence concomitant with an attenuation of Trx2 processing in which Trx2 presequence [i.e., mitochondrial targeting signal peptide (MTS)] is cleaved to generate a mature form. Mutation analyses indicate that Trx2 processing is mediated by mitochondrial processing peptidase (MPP) and mitochondrial intermediate peptidase (MIP)-recognition sites within the MTS. Interestingly, a mutation at a SUMO- interacting motif (SIM), but not the catalytic sites within the mature Trx2 protein, completely blocks Trx2 processing with no effect on Trx2 mitochondrial targeting. Consistently, chemical inhibition of protein SUMOylation attenuates, while SUMOylation agonist promotes, Trx2 processing. Moreover, we identify the α–MPP subunit is a SUMOylated protein that potentially mediates Trx2-binding and cleavage. Furthermore, the unprocessed form of Trx2-SIM is unable to protect cells from both ROS generation and oxidative stress-induced cellular senescence.ConclusionOur study reveals that a unique SUMO-interacting motif of Trx2 is critical for its mitochondrial processing and subsequent anti-oxidant/antisenescence activities.
Highlights
Cardiovascular diseases (CVD) are and will remain the leading cause of global death and disability (Benjamin et al, 2017; Xue et al, 2017)
Approach and Results: Here we show that excess reactive oxygen species (ROS) induce endothelial cell senescence concomitant with an attenuation of thioredoxin 2 (Trx2) processing in which Trx2 presequence [i.e., mitochondrial targeting signal peptide (MTS)] is cleaved to generate a mature form
Mutation analyses indicate that Trx2 processing is mediated by mitochondrial processing peptidase (MPP) and mitochondrial intermediate peptidase (MIP)-recognition sites within the MTS
Summary
Cardiovascular diseases (CVD) are and will remain the leading cause of global death and disability (Benjamin et al, 2017; Xue et al, 2017). CVD mortality rates increase with age, and the aging process poses the largest risk factor for the development of CVD (Finegold et al, 2013). Chronic exposure to CVD risk factors increases oxidative stress, which hastens the development of vascular endothelial senescence that could contribute to the pathogenesis of CVD (Voghel et al, 2007). Vascular endothelial cells senescence has been increasingly linked to both aging and age-related diseases, including heart failure, diabetes, and atherosclerosis (Minamino and Komuro, 2007; Voghel et al, 2007; Tian and Li, 2014; Katsuumi et al, 2018). Stress-induced premature senescence (SIPS) is induced by oxidative stress, oncogene activity, or suboptimal culture conditions, which occurs independently of a change of telomere length (Coleman et al, 2010). DNA damage marker phosphorylation of γH2A.X can be used to identify senescent cells (Munoz-Espin and Serrano, 2014)
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