Activation of gamma 2-AMPK Suppresses Ribosome Biogenesis and Protects Against Myocardial Ischemia/Reperfusion Injury

作者：Cao Yang; Bojjireddy Naveen; Kim Maengjo; Li Tao; Zhai Peiyong; Nagarajan Narayani; Sadoshima Junichi; Palmiter Richard D; Tian Rong^*

来源：Circulation Research, 2017, 121(10): 1182-+.

DOI：10.1161/CIRCRESAHA.117.311159

• AMP-activated protein kinases
• cell death
• endoplasmic reticulum
• ribosomes
• transcription factors

Rationale: AMPK (AMP-activated protein kinase) is a heterotrimeric protein that plays an important role in energy homeostasis and cardioprotection. Two isoforms of each subunit are expressed in the heart, but the isoform-specific function of AMPK remains unclear.
Objective: We sought to determine the role of gamma 2-AMPK in cardiac stress response using bioengineered cell lines and mouse models containing either isoform of the gamma-subunit in the heart.
Methods and Results: We found that gamma 2 but not gamma 1 or gamma 3 subunit translocated into nucleus on AMPK activation. Nuclear accumulation of AMPK complexes containing gamma 2-subunit phosphorylated and inactivated RNA Pol I (polymerase I)-associated transcription factor TIF-IA at Ser-635, precluding the assembly of transcription initiation complexes for rDNA. The subsequent downregulation of pre-rRNA level led to attenuated endoplasmic reticulum (ER) stress and cell death. Deleting gamma 2-AMPK led to increases in pre-rRNA level, ER stress markers, and cell death during glucose deprivation, which could be rescued by inhibition of rRNA processing or ER stress. To study the function of gamma 2-AMPK in the heart, we generated a mouse model with cardiac-specific deletion of gamma 2-AMPK (cardiac knockout [cKO]). Although the total AMPK activity was unaltered in cKO hearts because of upregulation of gamma 1-AMPK, the lack of gamma 2-AMPK sensitizes the heart to myocardial ischemia/reperfusion injury. The cKO failed to suppress pre-rRNA level during ischemia/reperfusion and showed a greater infarct size. Conversely, cardiac-specific overexpression of gamma 2-AMPK decreased ribosome biosynthesis and ER stress during ischemia/reperfusion insult, and the infarct size was reduced.
Conclusions: The gamma 2-AMPK translocates into the nucleus to suppress pre-rRNA transcription and ribosome biosynthesis during stress, thus ameliorating ER stress and cell death. Increased gamma 2-AMPK activity is required to protect against ischemia/reperfusion injury. Our study reveals an isoform-specific function of gamma 2-AMPK in modulating ribosome biosynthesis, cell survival, and cardioprotection.

• 出版日期2017-10-27
• 单位rutgers