MicroRNA-137 Is a Novel Hypoxia-responsive MicroRNA That Inhibits Mitophagy via Regulation of Two Mitophagy Receptors FUNDC1 and NIX

Abstract

Background: Mitophagy and microRNA both regulate the occurrence of neurodegenerative diseases and cancers. Results: MicroRNA-137, a hypoxia responsive microRNA, inhibits mitophagy via targeting two mitophagy receptors. Conclusion: A novel link between miR-137 and mitophagy has been revealed. Significance: Understanding mitophagy regulation and microRNA functions may provide new concepts to fight human diseases.

Autophagy machinery in the context of mammalian mitophagy

“…Nix, Bnip3 and FUNDC1 are mitochondrial outer membrane proteins which can directly bind to LC3. Nix is required for mitophagy in reticulocytes [50,51,53], and Bnip3/Nix and FUNDC1 act in hypoxia-induced mitophagy [46,49,[54][55][56]. The roles of these adapters are discussed elsewhere [33,62].…”

“…TBC1D15/TBC1D17 may inhibit uncontrolled elongation of isolation membranes thereby facilitating close enwrapping of mitochondria. Other factors that act like adapters include Nix/Bnip3 [46][47][48][49][50][51][52][53], FUNDC1 [54][55][56], HDAC6 [57,58], NDP52/TAX1BP1 [59,60] and SMURF1 [61] although the contribution of these proteins in Parkin-dependent mitophagy is not clear. Nix, Bnip3 and FUNDC1 are mitochondrial outer membrane proteins which can directly bind to LC3.…”

Organelle-Specific Initiation of Autophagy

“…Moreover, lysosomes play a key role in adaptive autophagy caused by an increased demand of metabolic intermediates. Chauhan et al, 2015;Knodler and Celli, 2011;Mandell et al, 2014 hypoxia mitophagy relies on the transactivation of BNIP3 and BNIP3L by HIF1, as well as on FUNDC1 Bellot et al, 2009;Chen et al, 2014Li et al, 2014Liu et al, 2014;Maxwell et al, 1999;Mazure and Pouyssé gur, 2009;Zhang et al, 2008 lipid droplets lipophagy contributes to hormone-and starvation-driven lipolysis Eid et al, 2013;Singh et al, 2009 protein aggregates aggrephagy relies on p62, OPTN, and ALFY Lamark and Johansen, 2012 ribosomes ribophagy not yet observed in mammalian cells Kraft et al, 2008 RNS ROS non-selective promote autophagy via an ATM/ LKB1 signaling pathway Alexander et al, 2010;Tripathi et al, 2013 Lysosomes amino acid deprivation non-selective stimulates autophagy via Ragulator/ MTORC1 signaling Bar-Peled et al, 2012;Rebsamen et al, 2015;Sancak et al, 2010;Wang et al, 2015;Zoncu et al, 2011 glucose deprivation non-selective stimulates autophagy via Ragulator/ LBK1/AMPK signaling Zhang et al, 2014 lysosomotropic agents lysophagy involves p62 Maejima et al, 2013;Hung et al, 2013 Peroxisomes responses to xenobiotic pexophagy involves PEX3, PEX14, NBR1, and ATG30 Burnett et al, 2015;Deosaran et al, 2013;Farré et al, 2008;Hara-Kuge and Fujiki, 2008;Yamashita et al, 2014 AKT1, v-akt murine thymoma viral oncogene homolog 1; ALFY (official name WDFY3), WD repeat and FYVE domain containing 3; AMPK (official name PRKA), protein kinase, AMP-activated; ATF, activating transcription factor; BECN1, beclin 1; BNIP3, BCL2/adenovirus E1B 19 kDa interacting protein 3; BNIP3L, BNIP3-like; CAMKKb (official name CAMKK2), calcium/calmodulin-dependent protein kinase kinase 2 beta; cAMP, cyclic AMP; CASP2, caspase 2; CCF, condensed chromatin fragment; CXCR4, chemokine (C-X-C motif) receptor 4; DAPK1, death-associated protein kina...…”

The receptor proteins: pivotal roles in selective autophagy

“…Except for the phosphorylation modification, the changes in FUNDC1 expression levels also affect the FUNDC1-mediated mitophagy. Li et al [62] demonstrated that microRNA-137 inhibits mitophagy by reducing the expression of mitophagy receptor FUNDC1 and NIX.…”