| First Author | Ahn M | Year | 2021 |
| Journal | Metabolism | Volume | 115 |
| Pages | 154431 | PubMed ID | 33181191 |
| Mgi Jnum | J:322058 | Mgi Id | MGI:6750983 |
| Doi | 10.1016/j.metabol.2020.154431 | Citation | Ahn M, et al. (2021) A requirement for PAK1 to support mitochondrial function and maintain cellular redox balance via electron transport chain proteins to prevent beta-cell apoptosis. Metabolism 115:154431 |
| abstractText | OBJECTIVE: p21 (Cdc42/Rac1) activated Kinase 1 (PAK1) is a candidate susceptibility factor for type 2 diabetes (T2D). PAK1 is depleted in the islets from T2D donors, compared to control individuals. In addition, whole-body PAK1 knock out (PAK1-KO) in mice worsens the T2D-like effects of high-fat diet. The current study tested the effects of modulating PAK1 levels only in beta-cells. MATERIALS/METHODS: beta-cell-specific inducible PAK1 KO (betaPAK1-iKO) mice were generated and used with human beta-cells and T2D islets to evaluate beta-cell function. RESULTS: betaPAK1-iKO mice exhibited glucose intolerance and elevated beta-cell apoptosis, but without peripheral insulin resistance. beta-cells from betaPAK-iKO mice also contained fewer mitochondria per cell. At the cellular level, human PAK1-deficient beta-cells showed blunted glucose-stimulated insulin secretion and reduced mitochondrial function. Mitochondria from human PAK1-deficient beta-cells were deficient in the electron transport chain (ETC) subunits CI, CIII, and CIV; NDUFA12, a CI complex protein, was identified as a novel PAK1 binding partner, and was significantly reduced with PAK1 knockdown. PAK1 knockdown disrupted the NAD(+)/NADH and NADP(+)/NADPH ratios, and elevated ROS. An imbalance of the redox state due to mitochondrial dysfunction leads to ER stress in beta-cells. PAK1 replenishment in the beta-cells of T2D human islets ameliorated levels of ER stress markers. CONCLUSIONS: These findings support a protective function for PAK1 in beta-cells. The results support a new model whereby the PAK1 in the beta-cell plays a required role upstream of mitochondrial function, via maintaining ETC protein levels and averting stress-induced beta-cell apoptosis to retain healthy functional beta-cell mass. |
