Linking Peroxiredoxin and Vacuolar-ATPase Functions in Calorie Restriction-Mediated Life Span Extension
Figure 2
Model for how CR postpones mitochondrial deficiency and aging via stimulating the function of vacuolar ATPase (v-ATPase) and the import of neutral amino acids into the vacuolar lumen. (a) Upon high glucose levels increased Ras-cAMP-PKA (Ras/PKA) activity inhibits v-ATPase function (arrow i) and thereby also the neutral aminoacid transporter Avt1 leading to the accumulation of neutral amino acids in the cytoplasm. Among these, leucine has been proposed to activate TORC1 through the leucyl-tRNA synthetase LeuRS and the Gtr1 GTPase (arrow iv). Cytosolic amino acid accumulation is thought to decrease mitochondrial function and to stimulate aging, possibly via increased TORC1 signaling. Increased TORC1 activity would also be expected to further inhibit v-ATPase function (arrow ii). Reduced v-ATPase function might also be expected to releive v-ATPase inhibition of Ras-PKA via cytosolic alkalinization (arrow iii). (b) CR and reduced glucose inhibition of v-ATPase function by Ras-PKA (arrow i) stimulates Avt1-mediated uptake of neutral amino acids. Lower cytoplasmic leucine levels would be expected to reduce TORC1 activity (arrow iv) and TORC1-mediated repression of v-ATPase activity (arrow ii). Similarly, increased v-ATPase function might be hypothesized to increase the inhibition of Ras-PKA activity, possibly via cytosolic acidification. Mitochondrial functions are maintained under conditions of reduced Ras/PKA and TORC1 activity as well as reduced levels cytosolic amino acids, which stimulates longevity. Arrows in black represent mechanisms at least in part experimentally verified to be in operation in aging cells [11] whereas arrows in grey indicate mechanisms inferred based on recent data implicating cytosolic pH and v-ATPase in the regulation of Ras-PKA [14, 16] as well as cytoplasmic leucine levels in the regulation of TORC1 signaling [13].
