Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR

Abstract

Mitochondria play a central role in cellular energy production, and their dysfunction can trigger a compensatory increase in glycolytic flux to sustain cellular ATP levels. Here, we studied the mechanism of this homeostatic phenomenon in C2C12 myoblasts. Acute (30 min) mitoenergetic dysfunction induced by the mitochondrial inhibitors piericidin A and antimycin A stimulated Glut1-mediated glucose uptake without altering Glut1 (also known as SLC2A1) mRNA or plasma membrane levels. The serine/threonine liver kinase B1 (LKB1; also known as STK11) and AMP-activated protein kinase (AMPK) played a central role in this stimulation. In contrast, ataxiatelangiectasia mutated (ATM; a potential AMPK kinase) and hydroethidium (HEt)-oxidizing reactive oxygen species (ROS; increased in piericidin-A-and antimycin-A-treated cells) appeared not to be involved in the stimulation of glucose uptake. Treatment with mitochondrial inhibitors increased NAD + and NADH levels (associated with a lower NAD + :NADH ratio) but did not affect the level of Glut1 acetylation. Stimulation of glucose uptake was greatly reduced by chemical inhibition of Sirt2 or mTOR-RAPTOR. We propose that mitochondrial dysfunction triggers LKB1-mediated AMPK activation, which stimulates Sirt2 phosphorylation, leading to activation of mTOR-RAPTOR and Glut1-mediated glucose uptake.

FR58P1a; a new uncoupler of OXPHOS that inhibits migration in triple-negative breast cancer cells via Sirt1/AMPK/β1-integrin pathway

“…Interestingly, the activation of Sirt1/AMPK axis by FR58P1a has a cyto-protective effect in TNBC cells, promoting cell survival and proliferation but inhibiting their ability to migrate. In non-tumoral MCF10A cells, the activation of Sirt1/AMPK axis by FR58P1a only induces an early metabolic remodeling toward glycolysis to maintain ATP levels as previously reported 65,66 , lacking pro-survival and anti-migratory effects. These results suggest that possible aberrant metabolic signaling accompanies Sirt1/AMPK activation in TNBC cells.…”

Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells

“…47, 48 Similarly, chronic (5 weeks) CI inhibition induced a fully glycolytic phenotype in primary skin fibroblasts, associated with an extreme sensitivity to glucose withdrawal. 49 These findings led us to propose that BAY-induced CI inhibition might, in addition to increasing cellular ROS levels, induce a shortage of glucose contributing to cell death.…”

Complex II phosphorylation is triggered by unbalanced redox homeostasis in cells lacking complex III

“…On the other hand, it has been widely demonstrated that organization of these complexes into supra-molecular structures, or supercomplexes, greatly enhances their stability and assembly [5], and also prevents excessive ROS generation [6]. Recent studies showed that the supercomplex association is highly dynamic, and finely tuned by different signaling pathways that are triggered by increased ROS/H 2 O 2 production [7,8], or by mito-energetic dysfunction [9]. This changing organization allows for metabolic compensatory responses that enable mitochondria to promptly sustain the needed levels of cellular ATP.…”