Figure 6.

A model for the role of Sit4p in the regulation mitochondrial function. In parental cells, dihydroceramides (dh-Cer) and phytoceramide (phyto-Cer) levels are kept low, preventing the dephosphorylation of hexokinase 2 (Hxk2p) in serine-15, indirectly regulated by the ceramide-activated protein phosphatase Sit4p. In sit4Δ cells, the increase of Hxk2p phosphorylation contributes to mitochondrial fitness, increasing oxidative stress resistance and chronological lifespan. In isc1Δ cells, the higher levels of dh-Cer- and phyto-Cer activate Sit4p leading to Hxk2p dephosphorylation. This results in mitochondrial dysfunction, leading to a disturbed redox homeostasis, premature aging and oxidative stress sensitivity. Other proteins regulated by Sit4p may also contribute to these phenotypes.