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Albumin prevents reactive oxygen species-induced mitochondrial damage, autophagy, and apoptosis during serum starvation

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Abstract

Aberrant levels of reactive oxygen species (ROS) rapidly generated from NADPH oxidase (NOX) activation can be cytotoxic due to activating pro-apoptotic signals. However, ROS also induce pro-survival autophagy through the engulfment of damaged mitochondria. This study is aimed at investigating the cytoprotective role of albumin against NOX/ROS-induced autophagy and apoptosis under serum starvation. Serum starvation induced apoptosis following a myeloid cell leukemia sequence 1 (Mcl-1)/Bax imbalance, loss of the mitochondrial transmembrane potential, and caspase activation accompanied by pro-survival autophagy following canonical inhibition of mammalian target of rapamycin complex 1 (mTORC1). Aberrant ROS generation, initially occurring through NOX, facilitated mitochondrial damage, autophagy, and apoptosis. Autophagy additionally regulated the accumulation of ROS-generating mitochondria. NOX/ROS permitted p38 mitogen-activated protein kinase (p38 MAPK)-regulated mitochondrial apoptosis, accompanied by non-canonical induction of autophagy. In addition, activation of glycogen synthase kinase (GSK)-3β by NOX/ROS-inactivated Akt facilitated a decrease in Mcl-1, followed by mitochondrial apoptosis as well as autophagy. Restoring albumin conferred an anti-oxidative effect against serum starvation-deregulated NOX, p38 MAPK, and Akt/GSK-3β/Mcl-1/caspase-3 signaling. Albumin also prevented autophagy by sustaining mTORC1. These results indicate an anti-oxidative role for albumin via preventing NOX/ROS-mediated mitochondrial signaling to stimulate apoptosis as well as autophagy. Autophagy, initially induced by canonical inhibition of mTORC1 and enhanced by non-canonical mitochondrial damage, acts physically as a pro-survival mechanism.

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Abbreviations

AIF:

Apoptosis-inducing factor

ASK:

Apoptosis signal regulating kinase

GSK:

Glycogen synthase kinase

JNK:

c-Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinase

Mcl:

Myeloid cell leukemia sequence

mTORC:

Mammalian target of rapamycin complex

MTP:

Mitochondrial transmembrane potential

NOX:

NADPH oxidase

OA:

Okadaic acid

PKC:

Protein kinase C

PPase:

Protein phosphatase

ROS:

Reactive oxygen species

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Acknowledgments

We thank the Immunobiology Core, Research Center of Clinical Medicine, National Cheng Kung University Hospital, for providing services that include training, technical support, and assistance with experimental design and data analysis using Flow Cytometry Core facilities. This work was supported by the grant NSC 96-2320-B-006-018-MY3 from the National Science Council, Taiwan.

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The authors state that they have no conflict of interest to disclose.

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Correspondence to Chiou-Feng Lin.

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Shu-Yu Liu and Chia-Ling Chen contributed equally to this work.

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Liu, SY., Chen, CL., Yang, TT. et al. Albumin prevents reactive oxygen species-induced mitochondrial damage, autophagy, and apoptosis during serum starvation. Apoptosis 17, 1156–1169 (2012). https://doi.org/10.1007/s10495-012-0758-6

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