FIGURE 4: Model of how spartin modulates mitochondrial energy metabolism. Spartin has a pro-survival effect in chronological aging yeast and requires key regulators in energy metabolism. Spartin interacts with the cytosolic glycolytic flux-enhancing phospho-fructo-kinase Pfk26 and partly depends on Pfk26 to promote longevity, possibly by regulating the availability of NADH and pyruvate for also mitochondrial metabolism. The mitochondrial external NADH dehydrogenase Nde1 oxidizes NADH to transfer electrons to complex II and thus promotes oxidative phosphorylation to produce ATP. Spartin interacts with Nde1 and fails to exert its pro-survival role in Dnde1 cells. The pyruvate dehydrogenase (PDH) complex converts pyruvate to acetyl-CoA (AcCoA), which feeds the tricarboxylic acid (TCA) cycle to produce NADH and FADH₂ serving again ATP production through oxidative phosphorylation. Pda1, the core enzyme of the PDH complex can be activated by phosphorylation through the phosphatase Ptc6 and inactivated by Pkp1 kinase. In the absence of Pda1 spartin does not promote longevity, but it can completely complement cell death due deletion of PTC6 and therefore mimics Ptc6 function. Whether spartin directly or indirectly (through associated metabolism) modulates PDH to promote cell survival remains to be investigates, In the presence of spartin cells may thus produce more ATP due to optimized oxidative phosphorylation. G6P, glucose-6-phophate. F2,6BP, fructose-2,6-biphosphate. F6P, fructose-6-phosphate. Pfk1, Phosphofructokinase 1. F1,6BP, fructose-1,6-biphophate.