Novel PGC-1α/ATF5 Axis Partly Activates UPRmt and Mediates Cardioprotective Role of Tetrahydrocurcumin in Pathological Cardiac Hypertrophy

Abstract

Mitochondrial unfolding protein response (UPRmt) effectively resists the pathological cardiac hypertrophy and improves the mitochondrial function. However, the specific activation mechanism and drugs that can effectively activate UPRmt in the cardiac muscle are yet to be elucidated. The aim of this study was to determine the regulation role of UPRmt on preventing pathological cardiac hypertrophy by tetrahydrocurcumin (THC) and explore its underlying molecular mechanism. Male C57BL/6J wild-type (WT) mice were divided into a control group and subjected to sham treatment for 4 weeks, and a test group which was subjected to transverse aortic constriction (TAC) surgery. Animals in the control and test group were orally administered THC (50 mg/kg) for 4 weeks after TAC procedure; an equivalent amount of saline was orally administered in the control sham-treated group and the TAC group. Subsequently, oxidative stress and UPRmt markers were assessed in these mice, and cardiac hypertrophy, fibrosis, and cardiac function were tested. Small interfering RNA (siRNA) targeting proliferator-activated receptor-gamma coactivator (PGC)-1α and activating transcription factor 5 (ATF5) were used to determine the UPRmt activation mechanism. THC supplement partly upregulated UPRmt effectors and inhibited TAC-induced oxidative stress compared with TAC-operated WT mice, thereby substantially attenuating contractile dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, PGC-1α knockdown blunted the UPRmt activation and the cardioprotective role of THC. The interaction between PGC-1α and ATF5 was tested in neonatal rat cardiac myocytes under normal conditions. The results showed that PGC-1α was an upstream effector of ATF5 and partly activated UPRmt. In vitro, phenylephrine- (PE-) induced cardiomyocyte hypertrophy caused ATF5 upregulating rather than downregulating corresponding to the downregulation of PGC-1α. The PGC-1α/ATF5 axis mediated the UPRmt activation and stress-resistance role of THC in vitro. Collectively, the present study provides the first evidence that PGC-1 and ATF5 can form a signaling axis to partly activate UPRmt that mediates the cardioprotective role of THC in pathological cardiac hypertrophy.

ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle

“…Our data also indicate that ATF5 is not required for the induction of PGC-1α signaling following acute exercise, confirming what has also been shown in cardiomyocytes during cardiac stress [49].…”

UPRmt activation improves pathological alterations in cellular models of mitochondrial diseases

“…Moreover, this molecule promoted the expression of genes participating in mitochondrial biogenesis, function and maintenance such as PGC1α , Nrf1 , ATP synthase , and COX4 , as well as that of genes contributing to ROS reduction, including Mitochondrial uncoupling protein 3 ( UCP3 ) and Superoxide dismutase 2 ( SOD2 ), and their up-stream regulator, peroxisome proliferator activated receptors ( PPAR ) delta and CREB-1 [ 106 ]. In fact, treatments that augment cGMP-dependent signalling cascades have been proposed to attenuate mitochondrial dysfunction [ 62 , 107 – 109 ]. Overall, we could prove the pleiotropic effect of tetracyclines on several mitochondrial hormesis-related pathways in which CREB/ATF proteins are involved.…”

Insight into the mitochondrial unfolded protein response and cancer: opportunities and challenges

“…Evidence indicating that the enhancement of UPR mt activity inhibits the death of cardiomyocytes induced by chronic pressure overload demonstrates the cardioprotective function of the UPR mt [ 22 ]. Activation of the PGC-1α/ATF5 axis is beneficial for the alleviation of pathological cardiac hypertrophy [ 198 ]. Activation of UPR mt signaling promotes neurogenesis in the brains of mice with amyotrophic lateral sclerosis (ALS) [ 23 ].…”