Figure 8. Sirt4-ANT2 interplay regulates energy homeostasis and mediates a retrograde signaling from mitochondria.

Sirt4-ANT2 interaction in the mitochondria is required for cellular ATP homeostasis. Sirt4-dependent increase in ATP reduces AMPK activity to mediate a retrograde signaling to affect ACC and PGC1α functions. In Sirt4 deficient conditions, ANT2-dependent uncoupling results in a reduction in cellular ATP levels and activates AMPK. Since acylation of ANT2 is known to uncouple mitochondria, we speculate that Sirt4 possesses a deacylase activity. AMPK activation in the absence of Sirt4 consequently leads to phosphorylation of ACC (inhibitory effect), which is known to reduce malonyl CoA levels in the cytosol and thus increase mitochondrial fatty acid uptake (via de-repression of CPT1). In addition, AMPK activation in the absence of Sirt4 increases the expression of PGC1α and its downstream targets involved in beta-oxidation and mitochondrial biogenesis. Together, we propose that Sirt4 in the mitochondria mediates a feedback control to regulate fatty acid metabolism and OXPHOS components.