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Investigating Mitochondrial Redox State Using NADH and NADPH Autofluorescence Free Radical Biology and Medicine 100 (2016) 53–65 Contents lists available at ScienceDirect Free Radical Biology and Medicine journal homepage: www.elsevier.com/locate/freeradbiomed Investigating mitochondrial redox state using NADH and NADPH autofluorescence Thomas S. Blacker a,b, Michael R. Duchen a,n a Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK b Department of Physics and Astronomy, University College London, London WC1E 6BT, UK article info abstract Article history: The redox states of the NAD and NADP pyridine nucleotide pools play critical roles in defining the activity Received 9 March 2016 of energy producing pathways, in driving oxidative stress and in maintaining antioxidant defences. Received in revised form Broadly speaking, NAD is primarily engaged in regulating energy-producing catabolic processes, whilst 2 August 2016 NADP may be involved in both antioxidant defence and free radical generation. Defects in the balance of Accepted 8 August 2016 these pathways are associated with numerous diseases, from diabetes and neurodegenerative disease to Available online 9 August 2016 heart disease and cancer. As such, a method to assess the abundance and redox state of these separate Keywords: pools in living tissues would provide invaluable insight into the underlying pathophysiology. Experi- Nadh mentally, the intrinsic fluorescence of the reduced forms of both redox cofactors, NADH and NADPH, has Nadph been used for this purpose since the mid-twentieth century. In this review, we outline the modern Mitochondria implementation of these techniques for studying mitochondrial redox state in complex tissue prepara- Redox fl Fluorescence tions. As the uorescence spectra of NADH and NADPH are indistinguishable, interpreting the signals Microscopy resulting from their combined fluorescence, often labelled NAD(P)H, can be complex. We therefore FLIM discuss recent studies using fluorescence lifetime imaging microscopy (FLIM) which offer the potential to discriminate between the two separate pools. This technique provides increased metabolic information from cellular autofluorescence in biomedical investigations, offering biochemical insights into the changes in time-resolved NAD(P)H fluorescence signals observed in diseased tissues. & 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 1. Introduction potentially powerful tool for interrogating the state of biochemical pathways in cells and tissues, but interpreting changes in auto- The pyridine nucleotide pools, nicotinamide adenine dinu- fluorescence in relation to the activity of metabolic pathways re- cleotide (NAD) and nicotinamide adenine dinucleotide phosphate mains a challenge [4–6]. (NADP), are crucial to the intracellular balance between the gen- In most cell types, the total pool of NAD (oxidised plus reduced eration of reactive oxygen species (ROS) and their neutralisation. forms) is larger than that of NADP. However, the primary role of The NAD pool participates in processes driving energy homo- NADP is as an electron donor in anabolic pathways. As this re- eostasis, generally associated with the subsequent production of quires the pool to be kept in a significantly reduced state, the ROS. The NADP pool, meanwhile, plays a primary role in main- NADPH/NADPþ ratio is maintained high [7]. In contrast, the role taining the antioxidant defences, but in some tissues may also of NAD as an electron acceptor in catabolic pathways requires the serve as a cofactor in free radical generating reactions [1]. Both pool to be maintained in an oxidised state. Therefore, the NADH/ “ ” NAD and NADP act as electron carriers , ferrying reducing NADþ ratio is kept low [8]. Thus, while the size of the total NAD equivalents between redox reactions taking place inside the cell. In pool may be greater than that of the NADP pool, the intracellular þ þ their oxidised forms, NAD and NADP , both molecules may concentrations of the reduced forms, NADH and NADPH, are ty- receive electrons by the addition of a hydride ion, producing the pically of a similar order of magnitude [9]. The spectral properties reduced forms, NADH and NADPH. These are intrinsically fluor- of these fluorescent forms of the cofactors are indistinguishable escent [2], a phenomenon that has been exploited as a label-free [10,11]. Thus, the mixed signal is often referred to as NAD(P)H [12]. method for monitoring the intracellular redox state of living cells The absorption and emission properties of NAD(P)H were first and tissues for more than 60 years [3]. The approach represents a described by Warburg et al. in the 1930's and 1940's [13]. The construction of instrumentation for the use of NAD(P)H fluores- n Corresponding author. cence as a reporter of redox state in living samples began in the http://dx.doi.org/10.1016/j.freeradbiomed.2016.08.010 0891-5849/& 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 54 T.S. Blacker, M.R. Duchen / Free Radical Biology and Medicine 100 (2016) 53–65 1950’s with the pioneering work of Chance et al. [14]. In the fol- the field of NAD(P)H fluorescence imaging and an overview of the lowing years, demonstrations of NAD(P)H fluorescence spectro- relevant biochemical pathways required to interpret the data that scopy were performed in isolated mitochondria [15], ex vivo cells such experiments generate. We therefore outline the primary [16] and in vivo organs [17]. The development of laser scanning mechanisms of NADH and NADPH production and consumption confocal microscopy in the 1970's added spatial resolution to NAD and introduce the basic photophysics of the cofactors before dis- (P)H fluorescence measurements [18,19], permitting assessment of cussing practical considerations required to apply NAD(P)H fluor- differences in the redox state between subcellular organelles or escence intensity measurements to probe the mitochondrial redox different cell types in a complex tissue [20]. In the 1990's, time- state. We give an overview of some recent applications of FLIM to resolved fluorescence measurements were applied to NAD(P)H for NAD(P)H measurements and describe our efforts, using this tech- the first time [21], allowing determination of the lifetime of the nique, to separate the contributions of NADH and NADPH to the autofluorescence in response to changes in redox state. Akin to an total autofluorescence signal in several models. As these reduced optical half-life, the fluorescence lifetime of a molecule is highly forms are equally abundant but play contrasting biochemical roles, sensitive to changes in its local environment [2], suggesting the this method provides crucial insights into the redox balance in possibility of quantitative reporting of biochemical changes asso- living biological systems, beyond those available from measure- ciated with the NAD and NADP pools from inside living systems ments of fluorescence intensity alone. without the addition of extrinsic fluorophores. The commerciali- sation of fluorescence lifetime add-ons to conventional confocal microscopes in the early 2000’s made fluorescence lifetime ima- 2. Biochemical foundations of NAD(P)H fluorescence ging microscopy (FLIM) widely accessible [22], leading to a rapid measurements growth in the NAD(P)H FLIM literature. The frequent observation of differences in NAD(P)H lifetime characteristics between healthy 2.1. The central role of NAD in mitochondrial energy transduction and neoplastic tissue has now put the development of clinical diagnostic devices at the forefront of this field [23–27]. Glycolysis, taking place in the cytosol, provides the most pri- Our purpose in this review is to provide both an introduction to mitive pathway for converting the chemical potential energy Fig. 1. The redox states of the mitochondrial NAD and NADP pools are determined by a range of interconnected pathways. The redox state of cytosolic NAD and NADP, determined by the activities of glycolysis, lactate dehydrogenase (LDH) and the pentose phosphate pathway (PPP), may be indirectly passed to the mitochondria via the malate-aspartate (MA) shuttle and citrate-α-ketoglutarate shuttles (Cα) respectively. These rely on the actions of the aspartate-glutamate (AGA) and malate α-ketoglutarate (MαA) antiporters and the citrate carrier (CC). Inside the mitochondria, pyruvate produced by glycolysis, imported via the mitochondrial pyruvate carrier (MPC), may be converted into acetyl CoA by the pyruvate dehydrogenase (PDH) complex, permitting its oxidation in the TCA cycle to produce NADH. This may then be used to produce ATP at the electron transport chain (ETC) or be converted into NADPH at the nicotinamide nucleotide transhydrogenase (NNT). NADPH may then be used to maintain the glutathione peroxidase (GPX) or peroxiredoxin (PRX) antioxidant systems via the glutathione (GR) and thioredoxin (TR) reductase enzymes. T.S. Blacker, M.R. Duchen / Free Radical Biology and Medicine 100 (2016) 53–65 55 stored in the bonds of glucose into usable energy in the form of gradient across the inner mitochondrial membrane [40,52] which adenosine triphosphate (ATP) [28–32]. As two ATP molecules are drives ATP synthesis by the F1FO-ATP synthase [53,54]. A single used in the early stages of the process, including by the insulin- mitochondrial NADH molecule may produce two to five ATP mo- activated hexokinase to utilise the negative charge of the phos- lecules through this mechanism [40,55], assuming that the pro- phate group to trap the substrate in the cell [33], the complete tons passed into the intermembrane space cannot leak back into conversion of glucose into pyruvate results in a net gain of two the mitochondrial matrix and that the electrons from NADH are ATP molecules [34]. However, as shown in Fig. 1, ATP is not the passed along the ETC without loss. In reality, both of these pro- only molecule to carry energy away from glycolysis. The oxidation cesses may decrease the efficiency of aerobic respiration.
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