Myristoylation confers noncanonical AMPK functions in autophagy selectivity and mitochondrial surveillance.
AMP-activated protein kinase (AMPK) plays a central role in cellular energy sensing and bioenergetics. However, the role of AMPK in surveillance of mitochondrial damage and induction of mitophagy remains unclear. We demonstrate herein that AMPK is required for efficient mitophagy. Mitochondrial damage induces a physical association of AMPK with ATG16-ATG5-12 and an AMPK-dependent recruitment of the VPS34 and ATG16 complexes with the mitochondria. Targeting AMPK to the mitochondria is both sufficient to induce mitophagy and to promote cell survival. Recruitment of AMPK to the mitochondria requires N-myristoylation of AMPKβ by the type-I N-myristoyltransferase 1 (NMT1). Our data support a spatiotemporal model wherein recruitment of AMPK in association with components of the VPS34 and ATG16 complex to damaged mitochondria regulates selective mitophagy to maintain cancer cell viability.
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Jiyong
J
Liang
1] Department of Medicine, Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA [2] Department of Pathology, Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China.
Zhi-Xiang
ZX
Xu
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Zhiyong
Z
Ding
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Yiling
Y
Lu
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Qinghua
Q
Yu
Department of Medicine, Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Kaitlin D
KD
Werle
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Ge
G
Zhou
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Yun-Yong
YY
Park
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Guang
G
Peng
Division of Medical Genetics, Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Michael J
MJ
Gambello
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Gordon B
GB
Mills
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000906:Antibodies; D001343:Autophagy / Q000502:physiology*; D002478:Cells, Cultured; D005347:Fibroblasts; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D010957:Plasmids; D034622:RNA Interference
D000906:Antibodies; D055372:AMP-Activated Protein Kinases