MiR-144-3p and Its Target Gene β-Amyloid Precursor Protein Regulate 1-Methyl-4-Phenyl-1,2-3,6-Tetrahydropyridine-Induced Mitochondrial Dysfunction

Abstract

MicroRNAs (miRNAs) have been reported to be involved in many neurodegenerative diseases. The present study focused on the role of hsa-miR-144-3p in one of the neurodegenerative diseases, Parkinson’s disease (PD). Our study showed a remarkable down-regulation of miR-144-3p expression in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated SH-SY5Y cells. MiR-144-3p was then overexpressed and silenced in human SH-SY5Y cells by miRNA-mimics and miRNA-inhibitor transfections, respectively. Furthermore, β-amyloid precursor protein (APP) was identified as a target gene of miR-144-3p via a luciferase reporter assay. We found that miR-144-3p overexpression significantly inhibited the protein expression of APP. Since mitochondrial dysfunction has been shown to be one of the major pathological events in PD, we also focused on the role of miR-144-3p and APP in regulating mitochondrial functions. Our study demonstrated that up-regulation of miR-144-3p increased expression of the key genes involved in maintaining mitochondrial function, including peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM). Moreover, there was also a significant increase in cellular ATP, cell viability and the relative copy number of mtDNA in the presence of miR-144-3p overexpression. In contrast, miR-144-3p silencing showed opposite effects. We also found that APP overexpression significantly decreased ATP level, cell viability, the relative copy number of mtDNA and the expression of these three genes, which reversed the effects of miR-144-3p overexpression. Taken together, these results show that miR-144-3p plays an important role in maintaining mitochondrial function, and its target gene APP is also involved in this process.

Biological and Clinical Relevance of microRNAs in Mitochondrial Diseases/Dysfunctions

“…In the same cells, miR-144-3p overexpression significantly inhibited the protein expression of b-amyloid precursor protein (APP). In the same study, noticeable increase in cellular ATP, cell viability, and the relative copy number of mitochondrial DNA was noted, suggesting that miR-144-3p plays an important role in maintaining mitochondrial function, along with its target gene APP (Li et al, 2016).…”

“…Furthermore, miR-34a inhibits the PPAR a signaling pathway by binding to sites in the 3¢ UTR of adipoR2 genes and also involved in the 5¢-adenosine monophosphateactivated protein kinase pathway in mitochondria (Wen et al, 2018). Li et al (2016) in their study showed a remarkable upregulation of miR-144-3p with increased expression of key genes involved in maintaining the mitochondrial function, including peroxisome proliferator-activated receptor g coactivator-1a (PGC-1a), nuclear respiratory factor 1, and mitochondrial transcription factor A. In the same cells, miR-144-3p overexpression significantly inhibited the protein expression of b-amyloid precursor protein (APP).…”

“…In this perspective, understanding the role of miRNAs in mitochondria is significant and it may open the gateway for the discovery or the identification of new prognostic, diagnostic, or therapeutic targets for mitochondrial dysfunction or its related diseases. Interestingly, many articles show that the potential impact of miRNAs as a biomarker for mitochondrial dysfunction and their interaction with surrounding molecular pathways ( Jeong et al, 2013;Jiang et al, 2013;Wang et al, 2014;Li et al, 2016;Liu et al, 2018).…”

Swimming attenuates d-galactose-induced brain aging via suppressing miR-34a-mediated autophagy impairment and abnormal mitochondrial dynamics

“…To this end, we determined the expression of the proteins associated with energy metabolism and autophagy functional status. Since mitochondrial biogenesis is regulated by the proliferator-activated receptor-␥ coactivator-1-␣ (PGC-1␣)-nuclear factor-E2-related factor 2 (Nrf2)mitochondrial transcription factor A (TFAM) signal pathway, the decreased expression of PGC-1␣, NRF-1, and TFAM was observed in AD (19,30). In the present study, we first measured the protein expression level of PGC-1␣ in hippocampal tissue.…”

Analysis of the Interactions of Neuronal Apoptosis Genes in the Associative Gene Network of Parkinson’s Disease

“…3, для которых в ANDSystem не было информации об их ассоциациях с БП. Гены TP53, JUN, BCL2 и APP достаточно активно обсуждаются в литературе в связи с БП (Rekha, Selvakumar, 2014;Li et al, 2016;Oh et al, 2016;Lu et al, 2017). Ген TP53 кодирует белок-опухолевый супрессор, который регулирует многие процессы, в том числе клеточный цикл, апоптоз, старение клетки, репарацию ДНК и метаболизм.…”