Reduced Glucose Sensation Can Increase the Fitness of Saccharomyces cerevisiae Lacking Mitochondrial DNA

Abstract

Damage to the mitochondrial genome (mtDNA) can lead to diseases for which there are no clearly effective treatments. Since mitochondrial function and biogenesis are controlled by the nutrient environment of the cell, it is possible that perturbation of conserved, nutrient-sensing pathways may successfully treat mitochondrial disease. We found that restricting glucose or otherwise reducing the activity of the protein kinase A (PKA) pathway can lead to improved proliferation of Saccharomyces cerevisiae cells lacking mtDNA and that the transcriptional response to mtDNA loss is reduced in cells with diminished PKA activity. We have excluded many pathways and proteins from being individually responsible for the benefits provided to cells lacking mtDNA by PKA inhibition, and we found that robust import of mitochondrial polytopic membrane proteins may be required in order for cells without mtDNA to receive the full benefits of PKA reduction. Finally, we have discovered that the transcription of genes involved in arginine biosynthesis and aromatic amino acid catabolism is altered after mtDNA damage. Our results highlight the potential importance of nutrient detection and availability on the outcome of mitochondrial dysfunction.

mPOS is a novel mitochondrial trigger of cell death – implications for neurodegeneration

“…This may be at least partially explained by its effect on the stability of the cytosolic proteome in addition to its role in processing unimported mitochondrial proteins. Similarly, the Dunn group found that a dot6Δ tod6Δ double mutant is q o -lethal [44]. DOT6 and TOD6 are transcriptional repressors of genes required for ribosomal biogenesis and protein synthesis in the TOR-signaling pathway.…”

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“…However, loss of mtDNA has also been shown to cause a reduction in ISC formation due to loss of membrane potential and impaired import of ISC biosynthesis enzymes. Hence, loss of mtDNA also activates the iron signaling cascade . Importantly, such conditions should affect not only ISC biosynthesis but also heme formation and hence it is interesting to note that each have their own unique signaling pathway (see below).…”

“…It is therefore not surprising that mitochondrial function is coupled to signaling responses controlling arginine biosynthesis. It was recently shown that genes involved in the synthesis of arginine were highly induced upon mtDNA loss . Moreover, a significant reduction in the expression of two genes involved in aromatic amino acid catabolism, ARO9 and ARO10 , occurred as a result of the loss of mtDNA.…”

“…Moreover, a significant reduction in the expression of two genes involved in aromatic amino acid catabolism, ARO9 and ARO10 , occurred as a result of the loss of mtDNA. Although the signaling events that are responsible for this response are yet to be elucidated, it was shown that these changes were reversed by inhibition of the glucose‐sensing PKA pathway . Loss of mtDNA results in impaired TCA cycle and OXPHOS, which can lead to impaired production of the carbon skeleton molecules that are involved in amino acid biosynthesis.…”

“…Loss of mtDNA results in impaired TCA cycle and OXPHOS, which can lead to impaired production of the carbon skeleton molecules that are involved in amino acid biosynthesis. Therefore, these changes in amino acid metabolism might be the result of the need for maintaining amino acid levels in cells lacking mtDNA .…”