Article ; Online: Caveolin-1 promotes mitochondrial health and limits mitochondrial ROS through ROCK/AMPK regulation of basal mitophagic flux.
2023 Volume 38, Issue 1, Page(s) e23343
Abstract: Caveolin-1 (CAV1), the main structural component of caveolae, is phosphorylated at tyrosine-14 (pCAV1), regulates signal transduction, mechanotransduction, and mitochondrial function, and plays contrasting roles in cancer progression. We report that ... ...
| Abstract | Caveolin-1 (CAV1), the main structural component of caveolae, is phosphorylated at tyrosine-14 (pCAV1), regulates signal transduction, mechanotransduction, and mitochondrial function, and plays contrasting roles in cancer progression. We report that CRISPR/Cas9 knockout (KO) of CAV1 increases mitochondrial oxidative phosphorylation, increases mitochondrial potential, and reduces ROS in MDA-MB-231 triple-negative breast cancer cells. Supporting a role for pCAV1, these effects are reversed upon expression of CAV1 phosphomimetic CAV1 Y14D but not non-phosphorylatable CAV1 Y14F. pCAV1 is a known effector of Rho-associated kinase (ROCK) signaling and ROCK1/2 signaling mediates CAV1 promotion of increased mitochondrial potential and decreased ROS production in MDA-MB-231 cells. CAV1/ROCK control of mitochondrial potential and ROS is caveolae-independent as similar results were observed in PC3 prostate cancer cells lacking caveolae. Increased mitochondrial health and reduced ROS in CAV1 KO MDA-MB-231 cells were reversed by knockdown of the autophagy protein ATG5, mitophagy regulator PINK1 or the mitochondrial fission protein Drp1 and therefore due to mitophagy. Use of the mitoKeima mitophagy probe confirmed that CAV1 signaling through ROCK inhibited basal mitophagic flux. Activation of AMPK, a major mitochondrial homeostasis protein inhibited by ROCK, is inhibited by CAV1-ROCK signaling and mediates the increased mitochondrial potential, decreased ROS, and decreased basal mitophagy flux observed in wild-type MDA-MB-231 cells. CAV1 regulation of mitochondrial health and ROS in cancer cells therefore occurs via ROCK-dependent inhibition of AMPK. This study therefore links pCAV1 signaling activity at the plasma membrane with its regulation of mitochondrial activity and cancer cell metabolism through control of mitophagy. |
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| MeSH term(s) | Male ; Humans ; Caveolin 1/genetics ; Caveolin 1/metabolism ; AMP-Activated Protein Kinases/genetics ; AMP-Activated Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Mechanotransduction, Cellular ; Mitochondria/metabolism ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Mitochondrial Proteins/metabolism ; rho-Associated Kinases/genetics ; rho-Associated Kinases/metabolism |
| Chemical Substances | Caveolin 1 ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Reactive Oxygen Species ; Mitochondrial Proteins ; ROCK1 protein, human (EC 2.7.11.1) ; rho-Associated Kinases (EC 2.7.11.1) |
| Language | English |
| Publishing date | 2023-12-07 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 639186-2 |
| ISSN | 1530-6860 ; 0892-6638 |
| ISSN (online) | 1530-6860 |
| ISSN | 0892-6638 |
| DOI | 10.1096/fj.202201872RR |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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