A REDD1/TXNIP pro-oxidant complex regulates ATG4B activity to control stress-induced autophagy and sustain exercise capacity

Abstract

Macroautophagy (autophagy) is a critical cellular stress response; however, the signal transduction pathways controlling autophagy induction in response to stress are poorly understood. Here we reveal a new mechanism of autophagy control whose deregulation disrupts mitochondrial integrity and energy homeostasis in vivo. Stress conditions including hypoxia and exercise induce reactive oxygen species (ROS) through upregulation of a protein complex involving REDD1, an mTORC1 inhibitor and the pro-oxidant protein TXNIP. Decreased ROS in cells and tissues lacking either REDD1 or TXNIP increases catalytic activity of the redox-sensitive ATG4B cysteine endopeptidase, leading to enhanced LC3B delipidation and failed autophagy. Conversely, REDD1/TXNIP complex expression is sufficient to induce ROS, suppress ATG4B activity and activate autophagy. In Redd1−/− mice, deregulated ATG4B activity and disabled autophagic flux cause accumulation of defective mitochondria, leading to impaired oxidative phosphorylation, muscle ATP depletion and poor exercise capacity. Thus, ROS regulation through REDD1/TXNIP is physiological rheostat controlling stress-induced autophagy.

Disruption of REDD1 gene ameliorates sepsis-induced decrease in mTORC1 signaling but has divergent effects on proteolytic signaling in skeletal muscle

“…The sepsisinduced decrement in ULK Ser 757 phosphorylation in WT mice and the prevention of this response in REDD1 Ϫ/Ϫ mice were associated with coordinate changes in mTORC1 activity and were consistent with the recognized role of mTOR in regulating autophagy (11,55). These results are also consistent with previous reports in which MEFs lacking REDD1 were protected from the serum deprivation (10 h)-induced decrease in mTORC1 activity, ULK1 Ser 757 phosphorylation, p62, and induction of autophagy (11,43). However, our data differ from those showing that the deletion of REDD1 does not prevent increased autophagy following acute dexamethasone administration (5).…”

Emerging role for regulated in development and DNA damage 1 (REDD1) in the regulation of skeletal muscle metabolism

“…While evidence of this mechanism was elucidated in nonmuscle cells in culture, similar results were reported in the soleus of male rats housed at simulated altitude (i.e., hypoxic conditions) for ϳ2 wk (35 (81). Interestingly, in this latter study, the induction of REDD1 was associated with increased autophagy in the hypoxic state, consistent with the emerging role of REDD1 in the regulation of autophagy (81,104). These data are in contrast to earlier human work in which simulated hypoxia increased REDD1 mRNA as well as phosphorylation of p70S6K1 (Thr 389 ) and Akt (Ser 473 ) compared with the time-matched normoxic condition (20).…”

“…Furthermore, it was presumed that the reduction in ATP production was due to impaired mitophagy throughout the life of these animals and subsequent accumulation of nonfunctional mitochondria (104). This conclusion was supported by the finding that mitochondrial DNA was greater in the muscle of mice lacking REDD1 (104). Whether the increase in autophagy was simply due to decreased mTORC1 signaling is unknown and requires further investigation.…”

“…Mouse embryonic fibroblasts (MEFs) lacking REDD1 were resistant to the induction of autophagy by stimuli including hypoxia and pharmacological mTORC1 inhibition (rapamycin and Torin2) (104). Based on these studies, it was proposed that REDD1 binds to the thioredoxin interacting protein (TXNIP) and inhibits the TRX1/2 thioredoxins, which function to reduce cellular levels of reactive oxygen species (ROS) (104). Thus, when the TRX1/2 proteins are inhibited, cellular ROS levels increase, thereby enhancing autophagic flux.…”

“…For example, it was concluded that autophagic flux and ATP production were reduced in skeletal muscle of REDD1 KO mice following a single bout of treadmill aerobic exercise (2 h in duration) relative to WT mice (104). Here, exercise increased the expression of LC3 II in the muscle of WT mice, whereas the accumulation of LC3 II was reduced in REDD1 KO mice (104). Furthermore, it was presumed that the reduction in ATP production was due to impaired mitophagy throughout the life of these animals and subsequent accumulation of nonfunctional mitochondria (104).…”