Mitochondrial Signaling: Forwards, Backwards, and In Between

Figure 2

Positive and negative regulators of the retrograde pathway. The retrograde pathway is constitutively inhibited by Mks1p as well as TOR1/2p/Lst8p which hyperphosphorylates (P) the Rtg1/3p heterodimer. Bmh1/2p stabilizes the phosphorylated Mks1p contributing to its activity and preventing its degradation. Mitochondrial stress activates Rtg2p which dephosphorylates Mks1p. Mks1p then dissociates from Bmh1/2p and is degraded by Grr1p. Rtg2p also inhibits the inhibitory factor Lst8p. Additionally, Lst8p is part of the TOR1/2p complex and is also controlled by canonical regulators of TOR. The disinhibition of the Rtg1/3p heterodimer allows dephosphorylation and translocation to the nucleus where it activates the RTG genes. The prototypical RTG gene CIT2 encodes peroxisomal citrate synthase (CIT2) which converts Acetyl-CoA and oxaloacetic acid (OAA) to citrate. This contributes nitrogen to the TCA cycle in order to maintain an adequate supply of α-ketoglutarate. Ultimately, this leads to production of glutamate which is the ultimate source of biosynthetic reactions in yeast. The plasma membrane amino acid sensor SPS inhibits Rtg2p in a negative feedback mechanism in the presence of excess glutamate.