Genome-wide Responses to Mitochondrial Dysfunction

Abstract

Mitochondrial dysfunction can lead to diverse cellular and organismal responses. We used DNA microarrays to characterize the transcriptional responses to different mitochondrial perturbations in Saccharomyces cerevisiae. We examined respiratory-deficient petite cells and respiratory-competent wild-type cells treated with the inhibitors of oxidative phosphorylation antimycin, carbonyl cyanide m-chlorophenylhydrazone, or oligomycin. We show that respiratory deficiency, but not inhibition of mitochondrial ATP synthesis per se, induces a suite of genes associated with both peroxisomal activities and metabolite-restoration (anaplerotic) pathways that would mitigate the loss of a complete tricarboxylic acid cycle. The array data suggested, and direct microscopic observation of cells expressing a derivative of green fluorescent protein with a peroxisomal matrix-targeting signal confirmed, that respiratory deficiency dramatically induces peroxisome biogenesis. Transcript profiling of cells harboring null alleles of RTG1, RTG2, or RTG3, genes known to control signaling from mitochondria to the nucleus, suggests that there are multiple pathways of cross-talk between these organelles in yeast.

Multiple bHLH proteins regulate CIT2 expression in Saccharomyces cerevisiae

“…One possible explanation is that phospholipid synthesis is regulated by inositol and phospholipids are a source of acetyl-coA, which is a substrate for citrate synthase (Epstein et al, 2001). Arguably, the regulation by phosphate was only observed under very specific conditions in our experiments (absence of INO2 or INO4 and ρ 0 ), which may not happen in nature.…”

“…Arguably, the regulation by phosphate was only observed under very specific conditions in our experiments (absence of INO2 or INO4 and ρ 0 ), which may not happen in nature. However, it is noteworthy that expression profiling of mitochondrial dysfunction does identify the PHO89 gene (Na + -dependent phosphate transporter) as a target, suggesting that mitochondrial function is coordinated with phosphate uptake (Epstein et al, 2001;Traven et al, 2001). Another possible explanation is that this is simply a mechanism to balance phospholipid synthesis (regulated by inositol) with energy production, since citrate synthase is the ratelimiting step in the TCA cycle.…”

“…Rtg1p and Rtg3p have both been shown to interact with Ino4p (Robinson and Lopes, 2000a). Expression profiling identified two PHO genes as targets of retrograde regulation (Epstein et al, 2001). Moreover, ENO1 (a target of the Sgc1p homodimer) is also regulated by Rtg1p and Rtg3p .…”

A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis

“…90 membrane potential by CCCP were also found to result in the repression of genes. 91 Thus, the definition of retrograde regulation includes nuclear responses to changes in the functional state of mitochondria. How do mitochondria control nuclear activities?…”

Genetic and genomic systems to study methylmalonic acidemia

“…The cycle may be viewed as enabling an organism to oxidize propionate to pyruvate. Yeast harboring mutations in the pdh gene, a putative methylcitrate dehydratase, are sensitive to exogenous propionate [48]. The exact basis for this sensitivity is not known but may be relevant to the understanding of the targets of propionyl-CoA toxicity in mammalian systems.…”