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

Abstract

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-γ coactivator α (PGC-1α)/Mt transcription factor A (TFAM or mtTFA) signaling pathway. Knockout of PGC-1α exacerbates DPN, whereas over-expression of human TFAM is protective. LY379268, a selective metabolomic glutamate receptor 2/3 (mGluR2/3) receptor agonist, also upregulates the SIRT1/PGC-1α/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-1α–TFAM pathway both from the perspective of pathogenesis and therapy in DPN.

Topical Delivery of Muscarinic Receptor Antagonists Prevents and Reverses Peripheral Neuropathy in Female Diabetic Mice

“…The therapeutic implications of cholinergic constraint of sensory neurons include the potential for muscarinic antagonists to promote nerve regeneration after injury and to enhance mitochondrial activity in neurons under metabolic stress. It is becoming increasingly apparent that a number of peripheral neuropathies, including those associated with diabetes (Fernyhough, 2015;Chandrasekaran et al, 2019), chemotherapy (Trecarichi and Flatters, 2019) and HIV infection (Roda and Hoke, 2019) share a common pathogenesis centered on impaired mitochondrial activity. In a recent study, mice lacking the M 1 R were protected from diabetes-induced neuropathy while subcutaneous injection of selective M 1 R antagonists prevented and reversed multiple functional and structural indices of peripheral neuropathy in rodent models of diabetes, chemotherapy-induced neuropathy and neuropathy caused by HIV-associated proteins (Calcutt et al, 2017).…”

Protective role of p53 in doxorubicin-induced cardiomyopathy as a mitochondrial disease

“…At the cellular signaling level, increasing tissue nicotinamide adenine dinucleotide (NAD + ) content by NMN has been reported to increase the expression of TFAM for mtDNA homeostasis via NAD + /sirtuin 1 (SIRT1)-mediated deacetylation and activation of PGC-1α, but this could also involve other SIRT family members. 9 In summary, the present study provides genetic evidence that p53 has a protective effect on the mitochondrial genome of the heart after doxorubicin exposure and that its regulation of mtDNA transcription may be critical for preventing cardiotoxicity ( Figure 1). Chromatin immunoprecipitation (ChIP) analysis in human myoblasts demonstrated that mutant p53 R175H can be recruited to an ETS2-binding site of TFAM via protein-protein interaction to increase its expression, analogous to a mechanism previously reported for the p53R2 gene.…”

Sirt1 Regulates Oxidative Stress in Oxygen-Glucose Deprived Hippocampal Neurons

“…The Sirt1/PGC-1 pathway can play a protective role by activating autophagy against oxidative stress-mediated ROS production in systemic endogenous stress syndrome (39). In diabetic peripheral neuropathy, overexpression of Sirt1 can increase axonal growth through Sirt1/ PGC-1α/ TFAM axis and improve mitochondrial oxidative metabolism (40). It has also been shown that Sirt1/PGC-1α signaling pathway can further regulate the role of uncoupling protein 2(UCP2) or Forkhead box protein O1(FOXO1) in reducing oxidative stress and neuronal apoptosis (41,42).…”