A requirement for PAK1 to support mitochondrial function and maintain cellular redox balance via electron transport chain proteins to prevent β-cell apoptosis.

Miwon Ahn, Eunjin Oh, Erika M McCown, Xin Wang, Rajakrishnan Veluthakal, Debbie C Thurmond

Metabolism: clinical and experimental 2021 Feb

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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 β-cells. β-cell-specific inducible PAK1 KO (βPAK1-iKO) mice were generated and used with human β-cells and T2D islets to evaluate β-cell function. βPAK1-iKO mice exhibited glucose intolerance and elevated β-cell apoptosis, but without peripheral insulin resistance. β-cells from βPAK-iKO mice also contained fewer mitochondria per cell. At the cellular level, human PAK1-deficient β-cells showed blunted glucose-stimulated insulin secretion and reduced mitochondrial function. Mitochondria from human PAK1-deficient β-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 β-cells. PAK1 replenishment in the β-cells of T2D human islets ameliorated levels of ER stress markers. These findings support a protective function for PAK1 in β-cells. The results support a new model whereby the PAK1 in the β-cell plays a required role upstream of mitochondrial function, via maintaining ETC protein levels and averting stress-induced β-cell apoptosis to retain healthy functional β-cell mass. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

Miwon Ahn, Eunjin Oh, Erika M McCown, Xin Wang, Rajakrishnan Veluthakal, Debbie C Thurmond. A requirement for PAK1 to support mitochondrial function and maintain cellular redox balance via electron transport chain proteins to prevent β-cell apoptosis. Metabolism: clinical and experimental. 2021 Feb;115:154431