Reduced nicotinamide adenine dinucleotide phosphate in redox balance and diseases: a friend or foe?

Abstract

The nicotinamide adenine dinucleotide (NAD⁺/NADH) and nicotinamide adenine dinucleotide phosphate (NADP⁺/NADPH) redox couples function as cofactors or/and substrates for numerous enzymes to retain cellular redox balance and energy metabolism. Thus, maintaining cellular NADH and NADPH balance is critical for sustaining cellular homeostasis. The sources of NADPH generation might determine its biological effects. Newly-recognized biosynthetic enzymes and genetically encoded biosensors help us better understand how cells maintain biosynthesis and distribution of compartmentalized NAD(H) and NADP(H) pools. It is essential but challenging to distinguish how cells sustain redox couple pools to perform their integral functions and escape redox stress. However, it is still obscure whether NADPH is detrimental or beneficial as either deficiency or excess in cellular NADPH levels disturbs cellular redox state and metabolic homeostasis leading to redox stress, energy stress, and eventually, to the disease state. Additional study of the pathways and regulatory mechanisms of NADPH generation in different compartments, and the means by which NADPH plays a role in various diseases, will provide innovative insights into its roles in human health and may find a value of NADPH for the treatment of certain diseases including aging, Alzheimer's disease, Parkinson's disease, cardiovascular diseases, ischemic stroke, diabetes, obesity, cancer, etc.

Keywords: Alzheimer’s disease; Parkinson’s disease; aging; cancer; diabetes; obesity.

Fig. 1

NAD⁺ synthesis via salvage pathway using NAM or NR, de novo pathway using tryptophan and preiss-handler pathway using NA as the precursors. NAD⁺, nicotinamide adenine dinucleotide, NAM, nicotinamide; NMN, nicotinamide mononucleotide; NR, nicotinamide riboside; NRK, NR kinase; NA, nicotinic acid; TDO, tryptophan 2,3-dioxygenase; IDO, indoleamine 2,3-dioxygenase; KFase, kynurenine formamidase; K3H, kynurenine‐3‐hydroxylase; AMS, 2‐amino‐3‐muconate‐semialdehyde; ACMS, 2‐amino‐3‐carboxy‐muconate‐semialdehyde; ACMSD, ACMS decarboxylase; NAMN, nicotinic acid mononucleotide; QPRT, quinolinate phosphoribosyltransferase; PRPP, phosphoribosyl pyrophosphate; NAAD, nicotinic acid adenine dinucleotide; NAPRT, nicotinic acid phosphoribosyltransferase; NMNAT, nicotinamide mononucleotide adenylyltransferase; NADSYN, NAD⁺ synthetases.

Fig. 2

Biosynthesis of NADPH from NAD⁺. NADK, NAD kinase; MNADK, mitochondrial NADK; G6PD, glucose-6-phosphate dehydrogenase; IDHc, cytosolic NADP-dependent isocitrate dehydrogenase; MEc, cytosolic NADP-dependent malic enzymes; IDHm, mitochondrial NADP-dependent isocitrate dehydrogenase; MEm, mitochondrial NADP-dependent malic enzymes; GDH, glutamate dehydrogenase; NNT, Nicotinamide nucleotide transhydrogenase; ETC, electron transport chain; ALDH1L1/ALDH1L2, aldehyde dehydrogenase (cytosol/mitochondrial); MTHFD1/2, methylenetetrahydrofolate dehydrogenase (cytosol/mitochondrial).

Fig. 3

Folate-mediated 1C metabolism in NADPH production. THF, tetrahydrofolate; MTHFD1, cytosolic methylene tetrahydrofolate dehydrogenase; MTHFD2, mitochondrial methylenetetrahydrofolate dehydrogenase; ALDH1L1, cytosolic aldehyde dehydrogenase; ALDH1L2, mitochondrial aldehyde dehydrogenase; SHMT1, cytosolic serine hydroxymethyltransferase; SHMT2, mitochondrial serine hydroxymethyltransferase.

Fig. 4

Pyruvate malate shuttle and pyruvate decarboxylation.

Fig. 5

Outline of the malate aspartate shuttle. ASPAR, aspartate; AST, aspartate aminotransferase; α-KGLUT, α-ketoglutarate; GLUT, glutamate; MDH, malate dehydrogenase; OAA, oxaloacetate. The net shuttle result is a transfer of the cytosolic NADH to the mitochondrial matrix.

Fig. 6

Isocitrate dehydrogenase shuttle. GLUD, glutamate dehydrogenase; NNT, Nicotinamide nucleotide transhydrogenase; α-KG, alpha-ketoglutarate.