Zc. Liu et Ra. Butow, A transcriptional switch in the expression of yeast tricarboxylic acid cycle genes in response to a reduction or loss of respiratory function, MOL CELL B, 19(10), 1999, pp. 6720-6728
The Hap2,3,4,5p transcription complex is required for expression of many mi
tochondrial proteins that function in electron transport and the tricarboxy
lic acid (TCA) cycle. We show that as the cells' respiratory function is re
duced or eliminated, the expression of four TCA cycle genes, CIT1, ACO1, ID
H1, and IDH2, switches from HAP control to control by three genes, RTG1, RT
G2, and RTG3. The expression of four additional TCA cycle genes downstream
of IDH1 and IDH2 is independent of the RTG genes. We have previously shown
that the RTG genes control the retrograde pathway, defined as a change in t
he expression of a subset of nuclear genes, e.g., the glyoxylate cycle CIT2
gene, in response to changes in the functional state of mitochondria, We s
how that the cis-acting sequence controlling RTG-dependent expression of CI
T1 includes an R box element, GTCAC, located 70 bp upstream of the Hap2,3,4
,5p binding site in the CIT1 upstream activation sequence. The R box is a b
inding site for Rtg1p-Rtg3p, a heterodimeric, basic helix-loop-helix/leucin
e zipper transcription factor complex. We propose that in cells with compro
mised mitochondrial function, the RTG genes take control of the expression
of genes leading to the synthesis of alpha-ketoglutarate to ensure that suf
ficient glutamate is available for biosynthetic processes and that increase
d flux of the glyoxylate cycle, via elevated CIT2 expression, provides a su
pply of metabolites entering the TCA cycle sufficient to support anabolic p
athways. Glutamate is a potent repressor of RTG-dependent expression of gen
es encoding both mitochondrial and nonmitochondrial proteins, suggesting th
at it is a specific feedback regulator of the RTG system.