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Effects of PQQ administration on retinal gross mitochondrial morphology in vivo. A Representative images of retinal cross sections from animals treated long-term with either vehicle or 20 mg/kg PQQ immunolabeled for TOMM20 (red) and counterstained with DAPI (blue). The DAPI was used for reference to crop GCL/NFL from IPL. Dashed lines demark the boundaries between GCL/NFL, IPL and INL on retinal sections. B–D Violin plots representing individual volume (B), surface area (C) and sphericity (D) of TOMM20-positive mitochondrial particles in GCL/NFL of vehicle or PQQ-treated animals. n = 555 vehicle and 812 PQQ disconnected particles from 7 different retinas per group. E–G Averaged volume sum (E), surface area sum (F) and count (G) per retina of TOMM20-positive mitochondrial particles in GCL/NFL. n = 7 retinas per group. H–J Violin plots showing individual TOMM20-positive mitochondrial particles volume (H), surface area (I) and sphericity (J) in IPL of vehicle or PQQ-treated animals. n = 1318 vehicle and 1361 PQQ disconnected particles from 7 different retinas per group. K–M Averaged volume sum (K), surface area sum (L) and count (M) per retina of TOMM20-positive mitochondrial particles in IPL. n = 7 retinas per group. For individual parameters, individual values of disconnected particles from each retina were analyzed together and a linear mixed effects model was applied to account for the multiple observations that come from the same sample. Scale bar = 20 μm. GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; NFL, nerve fiber layer. The red zoom depicts the inset of data points to optimally visualize the data distribution
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Retinal ganglion cells are highly metabolically active requiring strictly regulated metabolism and functional mitochondria to keep ATP levels in physiological range. Imbalances in metabolism and mitochondrial mechanisms can be sufficient to induce a depletion of ATP, thus altering retinal ganglion cell viability and increasing cell susceptibility t...
Citations
... Small aliquots of the remaining supernatants were pooled and used to create quality control (QC) samples. Re-suspension and measurements of the samples were performed as detailed in Canovai et al. (Canovai et al., 2023). Before randomized batch analysis, the samples were re-suspended in 10 + 10 µL methanol and elution solvent A. Each batch of samples was first analysed in positive mode and then the instrument was switched to negative mode and a second injection of each sample was performed. ...
... Mitochondrial membrane potential change of mouse cortical cells after treatment with EGCG and compound using JC-1 as previously described 51 . Four hemispheres from whole cortexes were collected and dissociated as described above. ...
Maintenance of NAD pools is critical for neuronal survival. The capacity to maintain NAD pools declines in neurodegenerative disease. We identify that low NMNAT2, the critical neuronal NAD producing enzyme, drives retinal susceptibility to neurodegenerative insults. As proof of concept, gene therapy over-expressing full length human NMNAT2 is neuroprotective. To pharmacologically target NMNAT2, we identify that epigallocatechin gallate (EGCG) can drive NAD production in neurons through an NMNAT2 and NMN dependent mechanism. We confirm this by pharmacological and genetic inhibition of the NAD-salvage pathway. EGCG is neuroprotective in rodent (mixed sex) and human models of retinal neurodegeneration. As EGCG has poor drug-like qualities, we use it as a tool compound to generate novel small molecules which drive neuronal NAD production and provide neuroprotection. This class of NMNAT2 targeted small molecules could have an important therapeutic impact for neurodegenerative disease following further drug development.
... PQQ deficiency alters lysine metabolism and plasma levels of amino acids such as threonine, serine, and glycine in vivo . In addition, the treatment with PQQ in healthy tissues such as the liver and optic nerve impacted amino acid metabolism, further supporting the role of PQQ in modulating amino acid metabolism in several tissues Canovai et al., 2023). PQQ might be involved in regulating lipid metabolism since the deficiency of this compound results in altered plasma lipid composition and expression of enzymes connected to lipid metabolism in the liver and heart (Bauerly et al., 2011). ...
... An enhanced expression in the nicotinamide phosphoribosyltransferase (NAMPT) gene (a key enzyme involved in NAD synthesis) has been identified concurrently with increased NAD + activity after the incubation of PQQ in HepG2 cell cultures, suggesting that in some contexts PQQ may enhance NAD production through the promotion of its biosynthetic pathways . As a support, the promoted increase in total NAD has been further documented in vivo, where Canovai et al. (2023) report an increased NAD content following PQQ administration in some districts of the visual system, such as the superior colliculus, in healthy mice. ...
... The capacity of PQQ in regulating physiological mitochondrial content was further confirmed in in vivo systems, where the deficiency of PQQ leads to reduced mitochondrial number and function in the liver whilst having no apparent effect in the heart (Stites et al., 2006;Bauerly et al., 2011). In a recent study by Canovai et al. (2023), only a mild effect of PQQ administration on mitochondrial content in healthy retinal tissues was demonstrated after neither a short nor a long-term treatment, reporting only a small variation in NADH:Ubiquinone Oxidoreductase Subunit B8 (NDUFB8; a mitochondrial complex I marker) expression without any evident activation of mitochondrial biogenesis machinery. Taken together, these in vivo studies further suggest the context dependency of PQQ effectiveness in increasing mitochondrial content previously shown in in vitro experiments. ...
Pyrroloquinoline quinone is a quinone described as a cofactor for many bacterial dehydrogenases and is reported to exert an effect on metabolism in mammalian cells/ tissues. Pyrroloquinoline quinone is present in the diet being available in foodstuffs, conferring the potential of this compound to be supplemented by dietary administration. Pyrroloquinoline quinone's nutritional role in mammalian health is supported by the extensive deficits in reproduction, growth, and immunity resulting from the dietary absence of pyrroloquinoline quinone, and as such, pyrroloquinoline quinone has been considered as a “new vitamin”. Although the classification of pyrroloquinoline quinone as a vitamin needs to be properly established, the wide range of benefits for health provided has been reported in many studies. In this respect, pyrroloquinoline quinone seems to be particularly involved in regulating cell signaling pathways that promote metabolic and mitochondrial processes in many experimental contexts, thus dictating the rationale to consider pyrroloquinoline quinone as a vital compound for mammalian life. Through the regulation of different metabolic mechanisms, pyrroloquinoline quinone may improve clinical deficits where dysfunctional metabolism and mitochondrial activity contribute to induce cell damage and death. Pyrroloquinoline quinone has been demonstrated to have neuroprotective properties in different experimental models of neurodegeneration, although the link between pyrroloquinoline quinone-promoted metabolism and improved neuronal viability in some of such contexts is still to be fully elucidated. Here, we review the general properties of pyrroloquinoline quinone and its capacity to modulate metabolic and mitochondrial mechanisms in physiological contexts. In addition, we analyze the neuroprotective properties of pyrroloquinoline quinone in different neurodegenerative conditions and consider future perspectives for pyrroloquinoline quinone's potential in health and disease.
