Autophagy proteins LC3B, ATG5 and ATG12 participate in quality control after mitochondrial damage and influence life span

Institute for Cell Biology and Neuroscience, Center of Excellence Frankfurt-Macromolecular Complexes, Goethe University, Frankfurt/Main, Germany.
Autophagy (Impact Factor: 11.75). 01/2012; 8(1):47-62. DOI: 10.4161/auto.8.1.18174
Source: PubMed


Mitochondrial health is maintained by the quality control mechanisms of mitochondrial dynamics (fission and fusion) and mitophagy. Decline of these processes is thought to contribute to aging and neurodegenerative diseases. To investigate the role of mitochondrial quality control in aging on the cellular level, human umbilical vein endothelial cells (HUVEC) were subjected to mitochondria-targeted damage by combining staining of mitochondria and irradiation. This treatment induced a short boost of reactive oxygen species, which resulted in transient fragmentation of mitochondria followed by mitophagy, while mitochondrial dynamics were impaired. Furthermore, targeted mitochondrial damage upregulated autophagy factors LC3B, ATG5 and ATG12. Consequently these proteins were overexpressed in HUVEC as an in vitro aging model, which significantly enhanced the replicative life span up to 150% and the number of population doublings up to 200%, whereas overexpression of LAMP-1 did not alter the life span. Overexpression of LC3B, ATG5 and ATG12 resulted in an improved mitochondrial membrane potential, enhanced ATP production and generated anti-apoptotic effects, while ROS levels remained unchanged and the amount of oxidized proteins increased. Taken together, these data relate LC3B, ATG5 and ATG12 to mitochondrial quality control after oxidative damage, and to cellular longevity.

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    • "An increase in p62 protein levels has also been found in HeLa cells (Sarraf et al. 2013) and MEFs (Ichimura et al. 2013) following treatment with depolarising agents CCCP and valinomycin respectively . An increase in autophagy proteins ATG5, ATG12 and LC3B has also been noted in HUVECs following induction of mitophagy by DNA damage, although the authors did not investigate p62 (Mai et al. 2012). During the submission process of this paper, TFEB and two other homologues (MITF and TFE3) from the same transcription factor family were reported to be activated in HeLa cells following mitophagy induction in a PINK1-and parkin-dependent manner (Nezich et al. 2015). "
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    • "Interestingly, we found several specific characteristics of autophagy after BIX01294 treatment, including the appearance of membranous vacuoles and the accumulation of LC3B in autophagosome [47]–[49]. Similar results were observed in G9a-knockdown cells. Recently, it was reported that BIX01294 induces apoptosis in three neuroblastoma cell lines (LA1-55n, IMR-5, and NMB) [50], which was different from our findings. "
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