AMPK Functions as a Switch between PGC-1α-Dependent and -Independent Pathways Driven by SIRT1

Next, we determined the mechanisms that determine whether SIRT1 utilizes the PGC-1α-dependent or -independent pathways. Under conditions of low energy, AMPK-mediated phosphorylation of PGC-1α allows it to be deacetylated and activated by SIRT1 (Cantó et al., 2009, Gerhart-Hines et al., 2007, Ptitsyn et al., 2006), whereas under basal conditions, acetylation status is primarily regulated by the acetyltransferase GCN5 (Fernandez-Marcos and Auwerx, 2011). We speculated that the biphasic decline in OXPHOS subunits (in Figure 1L) might be due to AMPK. In time course experiments following SIRT1 deletion, AMPK activation occurred after 48 hr, well after the decline in VHL-TFAM and mitochondrial genes (Figures 1L–1M and 6A ) but coincident with the decline in nuclear-encoded OXPHOS genes and mitochondrial mass (see Figures 1L–1M). An AMPK dominant-negative adenovirus (AMPK-DN) prevented the decline of nuclear OXPHOS mRNAs at 48 hr (Figures 6B and 6C), whereas forced maintenance of TFAM prevented AMPK activation (Figures 6D, 5D, and 5E). Together, these results strongly suggest that AMPK is the switch between the PGC-1α-dependent and -independent pathways. In this model, AMPK activation occurs in the absence of SIRT1 only when ATP levels fall below a threshold. Consistent with this, AMPK was unchanged under fed conditions in the SIRT1 iKO mice and 22-month-old wild-type mice but was markedly increased in fasting animals, when we observe changes in both nuclear- and mitochondrially encoded OXPHOS genes (Figure 6E and 6F).