Role of mitochondria in diabetic peripheral neuropathy: Influencing the NAD+-dependent SIRT1-PGC-1α-TFAM pathway

Survival of human peripheral nervous system neurons and associated distal axons is highly dependent on energy. Diabetes invokes a maladaptation in glucose and lipid energy metabolism in adult sensory neurons, axons and Schwann cells. Mitochondrial (Mt) dysfunction has been implicated as an etiological factor in failure of energy homeostasis that results in a low intrinsic aerobic capacity within the neuron. Over time, this energy failure can lead to neuronal and axonal degeneration and results in increased oxidative injury in the neuron and axon. One of the key pathways that is impaired in diabetic peripheral neuropathy (DPN) is the energy sensing pathway comprising the nicotinamide-adenine dinucleotide (NAD(+))-dependent Sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator alpha (PGC-1 alpha)/Mt transcription factor A (TFAM or mtTFA) signaling pathway. Knockout of PGC-1 alpha exacerbates DPN, whereas overexpression of human TFAM is protective. LY379268, a selective metabolomic glutamate receptor 2/3 (mGluR2/3) receptor agonist, also upregulates the SIRT1/PGC-1 alpha/TFAM signaling pathway and prevents DPN through glutamate recycling in Schwann/satellite glial (SG) cells and by improving dorsal root ganglion (DRG) neuronal Mt function. Furthermore, administration of nicotinamide riboside (NR), a precursor of NAD(+), prevents and reverses DPN, in part by increasing NAD(+) levels and SIRT1 activity. In summary, we review the role of NAD(+), mitochondria and the SIRT1-PGC-1 alpha-TFAM pathway both from the perspective of pathogenesis and therapy in DPN.