CYB5R3: a key player in aerobic metabolism and aging?

Abstract

Aging results from a complex and not completely understood chain of processes that are associated with various negative metabolic consequences and ultimately leads to senescence and death. The intracellular ratio of pyridine nucleotides (NAD(+)/NADH), has been proposed to be at the center stage of age-related biochemical changes in organisms, and may help to explain the observed influence of calorie restriction and energy-sensitive proteins on lifespan in model organisms. Indeed, the NAD(+)/NADH ratios affect the activity of a number of proteins, including sirtuins, which have gained prominence in the aging field as potential mediators of the beneficial effects of calorie restriction and mediating lifespan. Here we review the activities of a redox enzyme (NQR1 in yeast and CYB5R3 in mammals) that also influences the NAD(+)/NADH ratio and may play a regulatory role that connects aerobic metabolism with aging.

Keywords: /NADH; NAD; NQR1; cytochrome b; lifespan; reductase; respiration.

Figure 1.. Role of the different characters to guarantee the availability of NAD+ to consumers maintaining at the same time the cellular redox homeostasis through a balanced NAD ⁺/NADH ratio.

Figure 2.. MRC-5 normal human diploid fibroblasts were CYB5R3-silenced (KO cells) and cultured in DMEM medium supplemented with FBS 10%.

(A) Cell growth and CYB5R3 protein levels after five days of CYB5R3-silencing are shown. (B) Oxygen consumption was measured in parallel in both control and CYB5R3-KO cells. (C) Percentage of senescence was determined by senescence-associated-β-galactosidase activity. (D) Total RNA was extracted in both control and CYB5R3-KO cells and PGC1α mRNA levels were obtained by real time PCR.

Figure 3.. Hypothesis of the regulatory connection between cytochrome b₅ reductase and sirtuin to maintain SIRT1 dependent respiration and cytosolic NAD⁺/NADH ratio.