Over the last two decades, cyclic nucleotide phosphodiesterases (PDEs) have emerged as biological targets for the treatment of a variety of illnesses, and a number of selective PDE inhibitors have been become available as therapeutic drugs. PDEs are enzymes that control a range of physiological and pathological processes by hydrolyzing the phosphodiester link to inactivate the second messenger cAMP and cGMP. Over 50 isoforms of the PDE family’s 11 members are produced by 21 genes. The regulatory domains particular to each PDE are located at the N-terminus, whereas the catalytic sections of all PDEs, which range in identity from 30% to 50%, are well-conserved at the C-terminus. In order to effectively treat type 2 diabetes, effective PDE inhibitors are currently being developed. Insulin secretion by pancreatic β-cells is regulated by glucose, hormones, and neurotransmitters, and cAMP functions as a critical second messenger to increase insulin production. According to a research, M-LP/Mpv17L (Mpv17-like protein) suppression induces an increase in mtDNA damage in human kidney and liver cells.
Previous studies showed that human hepatoma (HepG2) cells that were MLP/Mpv17L-knockout (M-LP/Mpv17L-KO) have notable reduction in mitochondrial transcription factor A (TFAM) protein, a vital component for maintenance and phosphorylation of mtDNA. Since TFAM degradation is sparked by PKA-dependent phosphorylation and subsequently ubiquitination, these findings showed that M-LP/Mpv17L is connected to the cAMP/protein kinase A (PKA) pathway. In M-LP/Mpv17L-KO cells, there was a decrease in overall cellular PDE activity and an increase in mitochondrial cAMP. As per an experiment, in vitro generated M-LP/Mpv17L displayed PDE activity, which was blocked by 3-isobutyl-1-methylxanthine (IBMX), a non-selective PDE inhibitor, suggesting that M-LP/Mpv17L acts as a PDE despite the absence of a catalytic region conserved in the PDE family. To further understand the physiological function of M-LP/Mpv17L as atypical PDE in-vivo, researchers created M-LP/Mpv17L-KO mice. The adult mice acquired phenotypic, increased β-cell mass, and enhanced glucose tolerance.
In a new study published in Biochimica et Biophysica Acta – Molecular Basis of Disease Dr. Reiko Iida, Misuzu Ueki and Toshihiro Yasuda from University of Fukui in Japan, found that M-LP/Mpv17L controls the crosstalk between these pathways by phosphorylating β-catenin and GSK-3β in a PKA-dependent manner that is dependent on intracellular cAMP levels. M-LP/Mpv17L is one of the genes that is expressed differently depending on the age of the mouse kidney. M-LP/Mpv17L expression in kidneys increases gradually after puberty, reaches a peak throughout adulthood, and then gradually decreases with advancing age. Interestingly, the research team reported that the expression levels of M-LP/Mpv17L in tissues from foetuses (18–36 weeks) were 14.5–76.9% (mean 32.3%) lower than those in adults. One physiological effect of age-dependent expression in the liver was discovered through experiments with HepG2 cells. In HepG2 cells, M-LP/Mpv17L is mostly present in mitochondria, where it protects mtDNA against ROS-induced damage by preventing the phosphorylation and subsequent degradation of TFAM, a crucial component of mtDNA integrity.
It has been observed that the canonical Wnt signalling pathway is frequently inhibited in the adult pancreas, despite the fact that it is required for pancreatic endocrine development. Since M-LP/Mpv17L suppresses the Wnt pathway, its expression should be high during the adult stage when the Wnt pathway is suppressed and low during the foetal and infant phases when the Wnt pathway is active. Therefore, it is conceivable, according to experts, that M-LP/Mpv17L in pancreatic islets regulates the Wnt pathway in response to growth, development, and ageing. Improvement of glucose tolerance by activated PKA depends not only on enhanced glucose-stimulated insulin secretion (GSIS) through enhanced interactions between proteins involved in insulin-secreting vesicles and promotion of insulin and insulin secretion-related gene expression, but also on enhanced beta cell proliferation. Islet hyperplasia has been seen in people who have undergone a gastrectomy and have abnormally high blood levels of the hormone GLP-1, proving that incretin has a proliferative effect on β-cells.
The new study by Dr. Reiko Iida and colleagues discovered that M-LP/Mpv17L reduction promoted β-cell growth in the same way that incretins do and improved glucose tolerance.. These findings point to M-LP/Mpv17L as a potential therapeutic target for improving the function of β-cells.
Iida R, Ueki M, Yasuda T. Deficiency of M-LP/Mpv17L leads to development of β-cell hyperplasia and improved glucose tolerance via activation of the Wnt and TGF-β pathways. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2022 Mar 1;1868(3):166318.