During growth on fermentable substrates, such as glucose, pyruvate, which is the end-product of glycolysis, can be used to generate acetylCoA in the cytosol via acetaldehyde and acetate, or in mitochondria by direct oxidative decarboxylation. In the latter case, the mitochondrial pyruvate carrier (MPC) is responsible for pyruvate transport into mitochondrial matrix space. During chronological aging, yeast cells which lack the major structural subunit Mpc1 display a reduced lifespan accompanied by an age-dependent loss of autophagy. Here, we show that the impairment of pyruvate import into mitochondria linked to Mpc1 loss is compensated by a flux redirection of TCA cycle intermediates through the malic enzyme-dependent alternative route. In such a way, the TCA cycle operates in a “branched” fashion to generate pyruvate and is depleted of intermediates. Mutant cells cope with this depletion by increasing the activity of glyoxylate cycle and of the pathway which provides the nucleocytosolic acetyl-CoA. Moreover, cellular respiration decreases and ROS accumulate in the mitochondria which, in turn, undergo severe damage. These acquired traits in concert with the reduced autophagy restrict cell survival of the mpc1∆ mutant during chronological aging. Conversely, the activation of the carnitine shuttle by supplying acetyl-CoA to the mitochondria is sufficient to abrogate the short-lived phenotype of the mutant

Orlandi, I., PELLEGRINO COPPOLA, D., Vai, M. (2014). Rewiring yeast acetate metabolism through MPC1 loss of function leads to mitochondrial damage and decreases chronological lifespan. MICROBIAL CELL, 1(12), 393-405 [10.15698/mic2014.12.178].

Rewiring yeast acetate metabolism through MPC1 loss of function leads to mitochondrial damage and decreases chronological lifespan

ORLANDI, IVAN
Primo
;
PELLEGRINO COPPOLA, DAMIANO
Secondo
;
VAI, MARINA
Ultimo
2014

Abstract

During growth on fermentable substrates, such as glucose, pyruvate, which is the end-product of glycolysis, can be used to generate acetylCoA in the cytosol via acetaldehyde and acetate, or in mitochondria by direct oxidative decarboxylation. In the latter case, the mitochondrial pyruvate carrier (MPC) is responsible for pyruvate transport into mitochondrial matrix space. During chronological aging, yeast cells which lack the major structural subunit Mpc1 display a reduced lifespan accompanied by an age-dependent loss of autophagy. Here, we show that the impairment of pyruvate import into mitochondria linked to Mpc1 loss is compensated by a flux redirection of TCA cycle intermediates through the malic enzyme-dependent alternative route. In such a way, the TCA cycle operates in a “branched” fashion to generate pyruvate and is depleted of intermediates. Mutant cells cope with this depletion by increasing the activity of glyoxylate cycle and of the pathway which provides the nucleocytosolic acetyl-CoA. Moreover, cellular respiration decreases and ROS accumulate in the mitochondria which, in turn, undergo severe damage. These acquired traits in concert with the reduced autophagy restrict cell survival of the mpc1∆ mutant during chronological aging. Conversely, the activation of the carnitine shuttle by supplying acetyl-CoA to the mitochondria is sufficient to abrogate the short-lived phenotype of the mutant
Articolo in rivista - Articolo scientifico
acetyl-CoA, chronological aging, Mcp1, mitochondria, pyruvate, Saccharomyces cerevisiae
English
393
405
13
Orlandi, I., PELLEGRINO COPPOLA, D., Vai, M. (2014). Rewiring yeast acetate metabolism through MPC1 loss of function leads to mitochondrial damage and decreases chronological lifespan. MICROBIAL CELL, 1(12), 393-405 [10.15698/mic2014.12.178].
Orlandi, I; PELLEGRINO COPPOLA, D; Vai, M
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/56289
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