Abstract
Autophagy is a catabolic pathway that provides self-nourishment and maintenance of cellular homeostasis. Autophagy is a fundamental cell protection pathway through metabolic recycling of various intracellular cargos and supplying the breakdown products. Here, we report an autophagy function in governing cell protection during cellular response to energy crisis through cell metabolic rewiring. We observe a role of selective type of autophagy in direct activation of cyclic AMP protein kinase A (PKA) and rejuvenation of mitochondrial function. Mechanistically, autophagy selectively degrades the inhibitory subunit RI of PKA holoenzyme through A-kinase-anchoring protein (AKAP) 11. AKAP11 acts as an autophagy receptor that recruits RI to autophagosomes via LC3. Glucose starvation induces AKAP11-dependent degradation of RI, resulting in PKA activation that potentiates PKA-cAMP response element-binding signaling, mitochondria respiration, and ATP production in accordance with mitochondrial elongation. AKAP11 deficiency inhibits PKA activation and impairs cell survival upon glucose starvation. Our results thus expand the view of autophagy cytoprotection mechanism by demonstrating selective autophagy in RI degradation and PKA activation that fuels the mitochondrial metabolism and confers cell resistance to glucose deprivation implicated in tumor growth.
| Original language | English (US) |
|---|---|
| Article number | e2020215118 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 118 |
| Issue number | 14 |
| DOIs | |
| State | Published - Apr 6 2021 |
Funding
ACKNOWLEDGMENTS. We thank Dr. Estela Area-Gomez and Dr. Cristina Guardia-Laguarta for assisting in mitochondria imaging analysis, Dr. William Janssen and Allison Sowa for assisting in mitochondrial EM analysis, Dr. Jerry Chipuk and Madhavika N. Serasinghe for assisting in seahorse assay, and Dr. Xin Qi for antibody information. We also thank Dr. Esperanza Agullo Pascual for support in FRET assay, Dr. Wade Harper for kindly providing HEK 293T Atg7(−/−) and control, and Cell Signaling Technology for providing AKAP11 antibody. This work was supported by NIH/NINDS (National Institute of Neurological Disorders and Stroke) (R01NS060123 and P50NS094733) (Z.Y.), MoST (2017YFE0120100) (J.-H.L.) and the Ramon Areces Foundation (M.B.R.). We are thankful to Dr. Bing Xia for insightful comments. We thank Dr. Dongxiao Liang for making the graphic model. We are also grateful to Dr. George Heaton and Steven P. Seegobin and other members in Yue’s laboratories for critical reading and discussion of the manuscript.
Keywords
- AKAP11
- Autophagy
- Cell survival
- Mitochondrial metabolism
- PKA
ASJC Scopus subject areas
- General
