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NQR1 controls lifespan by regulating the promotion of respiratory metabolism in yeast.
Aging Cell. 2009 Apr; 8(2):140-51
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06 Nov 2009
Interesting Hypothesis, New Finding
DOI: 10.3410/f.1166555.627562
In the present article by the groups of Rafael de Cabo (Baltimore, USA) and Plácido Navas (Sevilla, Spain) it is demonstrated that in yeast calorie restriction (CR) up-regulates plasma membrane NADH-Coenzyme Q (PMNQ) expression, and overexpression of this enzyme stimulates respiration and extends lifespan....Continue reading
In the present article by the groups of Rafael de Cabo (Baltimore, USA) and Plácido Navas (Sevilla, Spain) it is demonstrated that in yeast calorie restriction (CR) up-regulates plasma membrane NADH-Coenzyme Q (PMNQ) expression, and overexpression of this enzyme stimulates respiration and extends lifespan. The sequence CR -> PMNQ -> respiration -> lifespan is an attractive hypothesis to explain these observations.
CR extends lifespan in all organisms tested and this effect is associated with the up-regulation of respiration {1} and of PMNQ {2}. Yeast PMNQ is encoded by the essential gene NQR1/PGA3 and is homologous to the endoplasmic reticulum enzyme NADH-cytochrome b5 oxidoreductase, involved in lipid hydroxylation and de-saturation and encoded by the non-essential SCS7/FAH1 gene. The mechanisms for both the essential role of NQR1 and its effect on respiration are speculated to depend on the control of the cellular NAD+/NADH ratio. In this respect, the NAD+-dependent deacetylase Sir2 may be important. However, the question remains why an enzyme dedicated to the control of the NAD+/NADH ratio is needed and why normal metabolic reactions are not sufficient. Also, the physiological final acceptor(s) of NQR1 needs to be investigated. Concerning the pro-longevity role of respiration, it seems mitochondria respiration is an essential anti-oxidant system {3}.
CR extends lifespan in all organisms tested and this effect is associated with the up-regulation of respiration {1} and of PMNQ {2}. Yeast PMNQ is encoded by the essential gene NQR1/PGA3 and is homologous to the endoplasmic reticulum enzyme NADH-cytochrome b5 oxidoreductase, involved in lipid hydroxylation and de-saturation and encoded by the non-essential SCS7/FAH1 gene. The mechanisms for both the essential role of NQR1 and its effect on respiration are speculated to depend on the control of the cellular NAD+/NADH ratio. In this respect, the NAD+-dependent deacetylase Sir2 may be important. However, the question remains why an enzyme dedicated to the control of the NAD+/NADH ratio is needed and why normal metabolic reactions are not sufficient. Also, the physiological final acceptor(s) of NQR1 needs to be investigated. Concerning the pro-longevity role of respiration, it seems mitochondria respiration is an essential anti-oxidant system {3}.
References
1.
Genetic links between diet and lifespan: shared mechanisms from yeast to humans.
Nat Rev Genet 2007 Nov; 11(8):835-44
PMID: 17909538
2.
The importance of plasma membrane coenzyme Q in aging and stress responses.
Mitochondrion 2007 Jun; (7 Suppl):S34-40
PMID: 17482527
3.
Mitochondrial function is an inducible determinant of osmotic stress adaptation in yeast.
J Biol Chem 2009 Oct 30; 44(284):30307-17
PMID: 19720830
Disclosures
None declared
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Serrano R: F1000Prime Recommendation of [Jiménez-Hidalgo M et al., Aging Cell 2009, 8(2):140-51]. In F1000Prime, 06 Nov 2009; DOI: 10.3410/f.1166555.627562. F1000Prime.com/1166555#eval627562
F1000Prime Recommendations, Dissents and Comments for [Jiménez-Hidalgo M et al., Aging Cell 2009, 8(2):140-51]. In F1000Prime, 23 May 2013; F1000Prime.com/1166555
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The activity and expression of plasma membrane NADH coenzyme Q reductase is increased by calorie restriction (CR) in rodents. Although this effect is well-established and is necessary for CR's ability to delay aging, the mechanism is unknown. Here we show that the Saccharomyces cerevisiae homolog, NADH-Coenzyme Q reductase 1 (NQR1), resides at the plasma membrane and when overexpressed extends both replicative and chronological lifespan. We show that NQR1 extends replicative lifespan in a SIR2-dependent manner by shifting cells towards respiratory metabolism. Chronological lifespan extension, in contrast, occurs via an SIR2-independent decrease in ethanol production. We conclude that NQR1 is a key mediator of lifespan extension by CR through its effects on yeast metabolism and discuss how these findings could suggest a function for this protein in lifespan extension in mammals.
DOI: 10.1111/j.1474-9726.2009.00461.x
PMID: 19239415
