CAMP-induced Mitochondrial Compartment Biogenesis

Edgar D Yoboue,Eric Augier,Anne Galinier,Corinne Blancard,Benoît Pinson,Louis Casteilla,Michel Rigoulet,Anne Devin

doi:10.1074/jbc.m111.302786

Abstract

Cell fate and proliferation are tightly linked to the regulation of the mitochondrial energy metabolism. Hence, mitochondrial biogenesis regulation, a complex process that requires a tight coordination in the expression of the nuclear and mitochondrial genomes, has a major impact on cell fate and is of high importance. Here, we studied the molecular mechanisms involved in the regulation of mitochondrial biogenesis through a nutrient-sensing pathway, the Ras-cAMP pathway. Activation of this pathway induces a decrease in the cellular phosphate potential that alleviates the redox pressure on the mitochondrial respiratory chain. One of the cellular consequences of this modulation of cellular phosphate potential is an increase in the cellular glutathione redox state. The redox state of the glutathione disulfide-glutathione couple is a well known important indicator of the cellular redox environment, which is itself tightly linked to mitochondrial activity, mitochondria being the main cellular producer of reactive oxygen species. The master regulator of mitochondrial biogenesis in yeast (i.e. the transcriptional co-activator Hap4p) is positively regulated by the cellular glutathione redox state. Using a strain that is unable to modulate its glutathione redox state (Δglr1), we pinpoint a positive feedback loop between this redox state and the control of mitochondrial biogenesis. This is the first time that control of mitochondrial biogenesis through glutathione redox state has been shown.

Highlights

Mitochondrial biogenesis is a complex process, and its regulation is not well known
ADP1⁄7Pi ratio consists in an induction of mitochondrial biogenesis, as evidenced by the overall increase in mitochondrial mass within the cell and an increased activity of the HAP complex driven by a regulation in the amount of the master regulator of this complex: Hap4p
Further investigation of the molecular mechanisms involved in this process showed that a chronic decrease in ATP/ADP1⁄7Pi ratio induced an increase in the intracellular glutathione redox state

Summary

Background

Mitochondrial biogenesis is a complex process, and its regulation is not well known. Results: cAMP-induced mitochondrial biogenesis through a decrease in the cellular phosphate potential is due to an increase in the glutathione redox status. We studied the molecular mechanisms involved in the regulation of mitochondrial biogenesis through a nutrientsensing pathway, the Ras-cAMP pathway Activation of this pathway induces a decrease in the cellular phosphate potential that alleviates the redox pressure on the mitochondrial respiratory chain. Previous work from our laboratory has shown that an increase in mitochondrial reactive oxygen species production is involved in mitochondria-to-nucleus signaling and induces a decrease in the activity of the transcription factor complex HAP2/3/4/5 (HAP complex), which is involved in mitochondrial biogenesis [5,6,7,8,9] In these conditions, the cells sense the oxidative stress and respond to it by increasing the amount of antioxidant enzymes (i.e. superoxide dismutase and catalase), this increase is not sufficient to suppress the overflow of reactive oxygen species. The master regulator of mitochondrial biogenesis in yeast, the transcriptional co-activator Hap4p, is shown to be quantitatively regulated by the glutathione redox state (i.e. the more oxidized this redox state, the less Hap4p expressed)

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION