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.
Highlights
Autophagy, or self-digestion, is a process that begins with the formation of isolation membranes [1]
Examining the distribution in detail, we found that peaks of signals for leucine-rich pentatricopeptide repeat-containing (LRPPRC) and MitoTracker® Red CMXRos, a dye that labels mitochondria on the basis of their potentials, did not always overlap (Figure 1B)
LRPPRC distributes in specific sites of mitochondria, suggesting that some roles were unlikely to be associated with nuclear ribonucleoprotein complexes
Summary
Self-digestion, is a process that begins with the formation of isolation membranes [1]. The isolation membrane engulfs substrates including dysfunctional organelles, misfolded/aggregated proteins and/or other macromolecules to form autophagosomes which migrate along acetylated microtubules to fuse with lysosomes to generate autolysosomes in which substrates are degraded [1,2,3,4]. Autophagy initiation is regulated either by growth factors through the PI3K (phosphoinositide 3-kinase)/Akt/mTOR (mammalian target of rapamycin) pathway [7] or by nutrients through the LKB1/AMPK (AMP-activated protein kinase)/mTOR pathway [8,9]. Bcl-2 sequesters Beclin 1 and prevents its association with PI3KCIII (class III PI3K) to suppress autophagy initiation through the PI3K/Akt/mTOR pathway [7,10] or enhances levels of p27 to activate autophagy through the LKB1/AMPK/mTOR pathway [8,9]. Dysfunctional mitochondria are separated from the healthy ones and bind to the substrate receptor and LC3-II interactive protein p62 to be escorted into autophagosomes for lysosomal degradation [16,17]
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