Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase

TLDR

Akt/PKB is a key growth‑factor‑mediated survival kinase that protects mitochondria, but its anti‑apoptotic effect requires glucose metabolism through hexokinase binding to VDAC. The study investigates whether Akt’s protection of mitochondria depends on hexokinase‑mediated coupling of glucose metabolism to oxidative phosphorylation. Akt promotes hexokinase‑VDAC interaction at the outer mitochondrial membrane, thereby linking glucose metabolism to oxidative phosphorylation and regulating the mitochondrial permeability transition pore. Akt increases mitochondria‑associated hexokinase activity, and its anti‑apoptotic effect requires only the first committed step of glucose metabolism; ectopic hexokinase expression mimics Akt’s inhibition of cytochrome‑c release and apoptosis.

Abstract

The serine/threonine kinase Akt/PKB is a major downstream effector of growth factor-mediated cell survival. Activated Akt, like Bcl-2 and Bcl-xL, prevents closure of a PT pore component, the voltage-dependent anion channel (VDAC); intracellular acidification; mitochondrial hyperpolarization; and the decline in oxidative phosphorylation that precedes cytochrome c release. However, unlike Bcl-2 and Bcl-xL, the ability of activated Akt to preserve mitochondrial integrity, and thereby inhibit apoptosis, requires glucose availability and is coupled to its metabolism. Hexokinases are known to bind to VDAC and directly couple intramitochondrial ATP synthesis to glucose metabolism. We provide evidence that such coupling serves as a downstream effector function for Akt. First, Akt increases mitochondria-associated hexokinase activity. Second, the antiapoptotic activity of Akt requires only the first committed step of glucose metabolism catalyzed by hexokinase. Finally, ectopic hexokinase expression mimics the ability of Akt to inhibit cytochrome c release and apoptosis. We therefore propose that Akt increases coupling of glucose metabolism to oxidative phosphorylation and regulates PT pore opening via the promotion of hexokinase-VDAC interaction at the outer mitochondrial membrane.