ABSTRACT
HIG2A promotes cell survival under hypoxia and mediates the assembly of complex III and complex IV into respiratory chain supercomplexes. In the present study, we show that human HIGD2A and mouse Higd2a gene expressions are regulated by hypoxia, glucose, and the cell cycle-related transcription factor E2F1. The latter was found to bind the promoter region of HIGD2A. Differential expression of the HIGD2A gene was found in C57BL/6 mice in relation to tissue and age. Besides, the silencing of HIGD2A evidenced the modulation of mitochondrial dynamics proteins namely, OPA1 as a fusion protein increases, while FIS1, a fission protein, decreases. Besides, the mitochondrial membrane potential (ΔΨm) increased. The protein HIG2A is localized in the mitochondria and nucleus. Moreover, we observed that the HIG2A protein interacts with OPA1. Changes in oxygen concentration, glucose availability, and cell cycle regulate HIGD2A expression. Alterations in HIGD2A expression are associated with changes in mitochondrial physiology.
Subject(s)
Cell Cycle/physiology , Membrane Potential, Mitochondrial/physiology , Mitochondrial Dynamics/physiology , Mitochondrial Membranes/metabolism , Animals , Electron Transport Complex I/genetics , Humans , Mice, Inbred C57BL , Mitochondrial Proteins/metabolism , Neoplasm Proteins/metabolismABSTRACT
PARKIN (E3 ubiquitin ligase PARK2), PINK1 (PTEN induced kinase 1) and DJ-1 (PARK7) are proteins involved in autosomal recessive parkinsonism, and carcinogenic processes. In damaged mitochondria, PINK1's importing into the inner mitochondrial membrane is prevented, PARKIN presents a partial mitochondrial localization at the outer mitochondrial membrane and DJ-1 relocates to mitochondria when oxidative stress increases. Depletion of these proteins result in abnormal mitochondrial morphology. PINK1, PARKIN, and DJ-1 participate in mitochondrial remodeling and actively regulate mitochondrial quality control. In this review, we highlight that PARKIN, PINK1, and DJ-1 should be regarded as having an important role in Cancer Biology. The STRING database and Gene Ontology (GO) enrichment analysis were performed to consolidate knowledge of well-known protein interactions for PINK1, PARKIN, and DJ-1 and envisage new ones. The enrichment analysis of KEGG pathways showed that the PINK1/PARKIN/DJ-1 network resulted in Parkinson disease as the main feature, while the protein DJ-1 showed enrichment in prostate cancer and p53 signaling pathway. Some predicted transcription factors regulating PINK1, PARK2 (PARKIN) and PARK7 (DJ-1) gene expression are related to cell cycle control. We can therefore suggest that the interplay among PINK1/PARKIN/DJ-1 network during mitochondrial quality control in cancer biology may occur at the transcriptional level. Further analysis, like a systems biology approach, will be helpful in the understanding of PINK1/PARKIN/DJ-1 network.
