The molecular mechanism underlying mitophagy‐mediated hippocampal neuron apoptosis in diabetes‐related depression

• Published in: Journal of cellular and molecular medicine Vol. 25; no. 15; pp. 7342 - 7353
• Main Authors: Liu, Jian, Liu, Lin, Han, Yuan‐Shan, Yi, Jian, Guo, Chun, Zhao, Hong‐Qing, Ling, Jia, Wang, Yu‐Hong
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.08.2021; John Wiley and Sons Inc
• Subjects: Animals; Apoptosis; Autophagy; Cells, Cultured; Depression - etiology; Depression - metabolism; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - psychology; Diabetes‐related depression; Diabetic retinopathy; Enzymes; Glucose; GluR2; Glutamate; Glutamic acid receptors; Hippocampal neuron; Hippocampus; Hippocampus - cytology; Hippocampus - metabolism; Laboratory animals; Lasers; Male; Membrane potential; Mental depression; Mitochondria; Mitophagy; Monoamines; Neurons; Neurons - drug effects; Neurons - metabolism; Neurotransmitter Agents - metabolism; Original; Parkin; Parkin protein; Pathogenesis; Polyclonal antibodies; Rapamycin; Rats; Rats, Sprague-Dawley; Reactive oxygen species; Receptors, AMPA - agonists; Receptors, AMPA - metabolism; Rodents; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Ubiquitin-Protein Ligases - metabolism; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; United States > US; China; Hippocampal neuron; Diabetes-related depression; GluR2; Glutamate; Mitophagy; Apoptosis; Parkin
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.16763

Diabetes‐related depression (DD) is a major complication of diabetes mellitus. Our previous studies indicated that glutamate (Glu) and hippocampal neuron apoptosis are key signal and direct factor leading to diabetes‐related depression, respectively. However, the accurate pathogenesis remains to be unclear. We hypothesized that diabetes‐related depression might be associated with the mitophagy‐mediated hippocampal neuron apoptosis, triggered by aberrant Glu‐glutamate receptor2 (GluR2)‐Parkin pathway. To testify this hypothesis, here the rat model of DD in vivo and in vitro were both established so as to uncover the potential mechanism of DD based on mitophagy and apoptosis. We found that DD rats exhibit an elevated glutamate levels followed by monoamine neurotransmitter deficiency and depressive‐like behaviour, and DD modelling promoted autophagosome formation and caused mitochondrial impairment, eventually leading to hippocampal neuron apoptosis via aberrant Glu‐GluR2‐Parkin pathway. Further, in vitro study demonstrated that the simulated DD conditions resulted in an abnormal glutamate and monoamine neurotransmitter levels followed by autophagic flux increment, mitochondrial membrane potential reduction and mitochondrial reactive oxygen species and lactic dehydrogenase elevation. Interestingly, both GluR2 and mammalian target of rapamycin (mTOR) receptor blocker aggravated mitophagy‐induced hippocampal neuron apoptosis and abnormal expression of apoptotic protein. In contrast, both GluR2 and mTOR receptor agonist ameliorated those apoptosis in simulated DD conditions. Our findings revealed that mitophagy‐mediated hippocampal neuron apoptosis, triggered by aberrant Glu‐GluR2‐Parkin pathway, is responsible for depressive‐like behaviour and monoamine neurotransmitter deficiency in DD rats. This work provides promising molecular targets and strategy for the treatment of DD.