Epigenetic modification of miR-663 controls mitochondria-to-nucleus retrograde signaling and tumor progression

Abstract

The normal cellular function requires communication between mitochondria and the nucleus, termed mitochondria-to-nucleus retrograde signaling. Disruption of this mechanism has been implicated in the development of cancers. Many proteins are known modulators of retrograde signaling, but whether microRNAs (miRNAs) are also involved is unknown. We conducted an miRNA microarray analysis using RNA from a parental cell line, a Rho line lacking mitochondrial DNA (mtDNA) and a Rho line with restored mtDNA. We found that miR-663 was down-regulated in the mtDNA-depleted Rho line. mtDNA restoration reversed this miRNA to parental level, suggesting that miR-663 may be epigenetically regulated by retrograde signaling. By using methylation-specific PCR and bisulfite sequencing we demonstrate that miR-663 promoter is epigenetically regulated not only by genetic but also by pharmacological disruption of oxidative phosphorylation (OXPHOS). Restoration of OXPHOS Complex I inhibitor-induced miR-663 expression by -acetylcysteine suggested that reactive oxygen species (ROS) play a key role in epigenetic regulation of miR-663. We determined that miR-663 regulates the expression of nuclear-encoded respiratory chain subunits involved in Complexes I, II, III, and IV. miR-663 also controlled the expression of the Complexes I (NDUFAF1), II (SDHAF2), III (UQCC2), and IV (SCO1) assembly factors and was required for stability of respiratory supercomplexes. Furthermore, using luciferase assays, we found that miR-663 directly regulates UQCC2. The anti-miR-663 reduced OXPHOS complex activity and increased cellular proliferation and promoted tumor development in mice. We also found that increased miR-663 expression in breast tumors consistently correlates with increased patient survival. We provide the first evidence for miRNA controlling retrograde signaling, demonstrating its epigenetic regulation and its role in breast tumorigenesis.

ncRNAs: New Players in Mitochondrial Health and Disease?

“…Several miRNAs have been described as directly targeting the OXPHOS subunits or assembly factors ( Figure 6, Table 2B). It was shown that miR-663 positively regulates OXPHOS subunit and assembly factor protein levels by direct stabilization of complex III assembly factor UQCC2 (Carden et al, 2017). In breast cancer cell lines, mitochondrial dysfunction downregulates miR-663 through hypermethylation of its promoter, which leads to decreasing OXPHOS proteins levels and enzymatic activity and stability of supercomplexes, which promotes tumorigenesis (Carden et al, 2017).…”

MicroRNA-663 induces immune dysregulation by inhibiting TGF-β1 production in bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus

“…We further characterized miR-663 because this miRNA is potentially associated with immune functions 23 and relevant to SLE disease activity (Figure 1d). MiR-663 has been demonstrated to play a critical role in anti-malignancies [34][35][36] because it induces the differentiation but suppresses the proliferation and invasion of tumor cells. Moreover, miR-663 is important for the key events induced in endothelial cells by stress agents and oxidized lipids, 37 and thus it may have a potential role in the development of atherosclerosis.…”

Interplay Between Mitochondrial Oxidative Disorders and Proteostasis in Alzheimer’s Disease

“…Although, an overproduction of free radicals such as superoxide anion (O 2 − ) and hydroxyl radical (OH) can generate unrepaired damage to mtDNA (Han and Chen, 2013), many studies pointed out the regulation of nuclear components through ROS signaling (Larosa and Remacle, 2018). For example, mitochondrial ROS can upregulate the expression of assembly factors of I, II, III, and IV complexes (Carden et al, 2017). In this way, mitochondrial ROS communicate with the nucleus in a bidirectional fashion.…”