Mitochondrion-associated protein LRPPRC suppresses the initiation of basal levels of autophagy via enhancing Bcl-2 stability
Open Access
- 29 August 2013
- journal article
- Published by Portland Press Ltd. in Biochemical Journal
- Vol. 454 (3), 447-457
- https://doi.org/10.1042/bj20130306
Abstract
The mitochondrion-associated protein LRPPRC (leucine-rich pentatricopeptide repeat-containing) interacts with one of the microtubule-associated protein family members MAP1S (microtubule-associated protein 1 small form), originally named C19ORF5 (chromosome 19 open reading frame 5), to form a complex. MAP1S interacts with LC3 (light chain 3), the mammalian homologue of yeast autophagy marker ATG8 and one of the most important autophagy markers in mammalian cells, and helps the attachment of autophagosomes with microtubules for trafficking and recruitment of substrate mitochondria into autophagosomes for degradation. MAP1S activates autophagosomal biogenesis and degradation to remove misfolded/aggregated proteins and dysfunctional organelles such as mitochondria and suppress oxidative stress-induced genomic instability and tumorigenesis. Previously, various studies have attributed LRPPRC nucleic acid-associated functions. Instead, in the present study, we show that LRPPRC associates with mitochondria, interacts with Beclin 1 and Bcl-2 and forms a ternary complex to maintain the stability of Bcl-2. Suppression of LRPPRC leads to reduction in mitochondrial potential and reduction in Bcl-2. Lower levels of Bcl-2 lead to release of more Beclin 1 to form the Beclin 1–PI3KCIII (class III phosphoinositide 3-kinase) complex to activate autophagy and accelerate the turnover of dysfunctional mitochondria through the PI3K (phosphoinositide 3-kinase)/Akt/mTOR (mammalian target of rapamycin) pathway. The activation of autophagy induced by LRPPRC suppression occurs upstream of the ATG5–ATG12 conjugate-mediated conversion of LC3-I into LC3-II and has been confirmed in multiple mammalian cell lines with multiple autophagy markers including the size of GFP–LC3 punctate foci, the intensity of LC3-II and p62 protein and the size of the vacuolar structure. The activated autophagy enhances the removal of mitochondria through lysosomes. LRPPRC therefore acts to suppress the initiation of basal levels of autophagy to clean up dysfunctional mitochondria and other cellular debris during the normal cell cycle.Keywords
This publication has 60 references indexed in Scilit:
- LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAsThe EMBO Journal, 2011
- The Beclin 1 network regulates autophagy and apoptosisCell Death & Differentiation, 2011
- RNS2, a conserved member of the RNase T2 family, is necessary for ribosomal RNA decay in plantsProceedings of the National Academy of Sciences of the United States of America, 2011
- Leucine-Rich Pentatricopeptide-Repeat Containing Protein Regulates Mitochondrial TranscriptionBiochemistry, 2010
- Molecular dissection of the eukaryotic initiation factor 4E (eIF4E) export-competent RNPThe EMBO Journal, 2009
- Autophagy fights disease through cellular self-digestionNature, 2008
- Fission and selective fusion govern mitochondrial segregation and elimination by autophagyThe EMBO Journal, 2008
- Autophagy in the Pathogenesis of DiseaseCell, 2008
- Selective degradation of mitochondria by mitophagyArchives of Biochemistry and Biophysics, 2007
- The energy sensing LKB1–AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosisNature, 2007