Oxidative stress-induced mitophagy is suppressed by the miR-106b-93-25 cluster in a protective manner

Abstract

Increased reactive oxygen species levels in the mitochondrial matrix can induce Parkin-dependent mitophagy, which selectively degrades dysfunctional mitochondria via the autolysosome pathway. Phosphorylated mitofusin-2 (MFN2), a receptor of parkin RBR E3 ubiquitin-protein ligase (Parkin), interacts with Parkin to promote the ubiquitination of mitochondrial proteins; meanwhile, the mitophagy receptors Optineurin (OPTN) and nuclear dot protein 52 (NDP52) are recruited to damaged mitochondria to promote mitophagy. However, previous studies have not investigated changes in the levels of OPTN, MFN2, and NDP52 during Parkin-mediated mitophagy. Here, we show that mild and sustained hydrogen peroxide (H2O2) stimulation induces Parkin-dependent mitophagy accompanied by downregulation of the mitophagy-associated proteins OPTN, NDP52, and MFN2. We further demonstrate that H2O2 promotes the expression of the miR-106b-93-25 cluster and that miR-106b and miR-93 synergistically inhibit the translation of OPTN, NDP52, and MFN2 by targeting their 3’ untranslated regions. We further reveal that compromised phosphorylation of MYC proto-oncogene protein (c-Myc) at threonine 58 (T58) (producing an unstable form of c-Myc) caused by reduced nuclear glycogen synthase kinase-3 beta (GSK3β) levels contributes to the promotion of miR-106b-93-25 cluster expression upon H2O2 induction. Furthermore, miR-106b-mediated and miR-93-mediated inhibition of mitophagy-associated proteins (OPTN, MFN2, and NDP52) restrains cell death by controlling excessive mitophagy. Our data suggest that microRNAs (miRNAs) targeting mitophagy-associated proteins maintain cell survival, which is a novel mechanism of mitophagy control. Thus, our findings provide mechanistic insight into how miRNA-mediated regulation alters the biological process of mitophagy.

Optineurin-mediated mitophagy as a potential therapeutic target for intervertebral disc degeneration

“…OPTN expression was substantially increased in cells treated with H 2 O 2 compared with untreated control cells. This result is inconsistent with the findings of Zhang et al ( Zhang et al, 2021 ), who found that continuous administration of low concentrations of H 2 O 2 decreases OPTN expression ( Zhang et al, 2021 ); we believe this difference is due to differences in the cell types studied, the concentration of H 2 O 2 and the duration of treatment. We speculate that short-term oxidative stress causes cells to undergo stress, which promotes mitophagy to counteract the damaging stimulus, resulting in elevated OPTN expression, whereas long-term stress causes oxidative and antioxidant dysregulation, resulting in mitophagy failure.…”

miR‑141 impairs mitochondrial function in cardiomyocytes subjected to hypoxia/reoxygenation by targeting Sirt1 and MFN2

“…A major disadvantage is that the total number of miRNAs that can target Sirt1 and MFN2 is expanding. For example, miR-22, -34a, -9, -29c and -92a, as well as miR-141 can target Sirt1 [ (17,(42)(43)(44), and the results of the present study], while miR-195, -106b, -93 and -20b, as well as miR-141 can target MFN2 [ (45)(46)(47), and the results of the present study]. Specifically, miR-34a, miR-141 and miR-9 may influence Parkinson's disease pathogenic processes by targeting Sirt1 (17).…”

Differential co-expression network analysis with DCoNA reveals isomiR targeting aberrations in prostate cancer

“…Another prostate cancer-specific target of miR-93, MFN2, was shown to suppress breast and thyroid cancer progression through AKT signaling [45, 46]. The direct binding of miR-93 to 3’-UTR of MFN2 was also experimentally validated with luciferase reporter assays [47, 48].…”