Which signaling pathway senses energy stress and activates mitochondrial biogenesis, promoting oxidative capacity?

• A. AMPK
• B. PGC-1alpha
• C. mTOR
• D. NF-kB

Answer: (A)

Energy stress is sensed by AMPK. When cellular energy is low, the AMP/ATP ratio rises and AMPK becomes activated. Once on, AMPK shifts metabolism toward generating ATP and signals the cell to increase mitochondrial capacity. It does this mainly by activating PGC-1alpha, a transcriptional coactivator that drives the expression of genes involved in mitochondrial biogenesis and oxidative metabolism. AMPK can phosphorylate PGC-1alpha and also promote NAD+ production, which activates SIRT1 to deacetylate and further activate PGC-1alpha. The net effect is more mitochondria and greater oxidative capacity. In contrast, mTOR responds to nutrient availability to promote growth and is inhibited by AMPK during energy stress, not directly driving mitochondrial biogenesis. PGC-1alpha is a key effector of the program but is activated by AMPK rather than acting as the energy sensor itself, and NF-kB is more tied to inflammatory signaling.