Activation of the highly conserved 5′-adenosine monophosphate–activated protein kinase (AMPK) is a fundamental component of the response to stresses that threatens cellular viability and therefore modulates many aspects of cell metabolism.1 This serine/threonine protein kinase is activated after stresses that deplete cellular ATP levels such as low glucose, hypoxia, ischemia, and heat shock. AMPK activation positively regulates signaling pathways that replenish cellular ATP including fatty acid oxidation and autophagy, whereas it negatively regulates ATP-consuming biosynthetic processes including gluconeogenesis, and lipid and protein synthesis. A growing body of evidence, however, show that AMPK also responds to glucose deprivation and oxidants stress without altering energy nucleotide levels in a wide variety of cells. For example, physiologically or pathologically relevant concentrations of free radicals and oxidants such as superoxide anion-derived hydrogen peroxide and peroxynitrites can activate AMPK without altering AMP/ATP (redox sensor).2,3 In turn, oxidant-activated AMPK feedback suppresses superoxide anion production by inhibiting NAD(P)H (nicotinamide adenine dinucleotide phosphate) oxidase and mitochondria-derived oxidants (redox modulator). As such, AMPK is considered to be a sensor and master regulator of both energy and redox homeostasis.2,3 Article, see p 1182 AMPK is a heterotrimeric protein complex consisting of 3 subunits, α, β, and γ, each encoded by distinct genes. These isoforms play specific roles in AMPK stability and activity, and all 3 are necessary for full activity.1–3 The α subunit (2 isoforms) contains the catalytic site; β (2 isoforms) and γ subunits (3 isoforms) are regulatory subunits. If ATP generation is impaired or cellular demand is increased, a higher cellular AMP: ATP ratio causes AMP to displace ATP from the exchangeable sites. AMP or ADP (adenosine-5'-diphosphate) then binds the γ subunit of AMPK and activates the kinase by 3 main mechanisms: allosteric activation of the α catalytic …