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Akt‐Mediated Mitochondrial Oxidative Stress Induces Mitophagy and Development of Pulmonary Fibrosis
Author(s) -
Casey Jennifer,
Ryan Alan,
Murthy Shubha,
Carter A Brent
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.1015.6
Subject(s) - pink1 , mitophagy , parkin , protein kinase b , mitochondrion , microbiology and biotechnology , oxidative stress , pulmonary fibrosis , mitochondrial ros , chemistry , biology , cancer research , fibrosis , autophagy , signal transduction , medicine , apoptosis , endocrinology , biochemistry , disease , parkinson's disease
Macrophage mitochondrial oxidative stress is directly linked to pulmonary fibrosis. Mitophagy is the selective engulfment of dysfunctional mitochondria by autophagasomes and can be induced by mitochondrial oxidative stress. Oxidative stress can trigger the PINK1/Parkin pathway, which target mitochondria for mitophagy. Mitophagy is important for quality control for cell homeostasis. In this study we show Akt induces macrophage mitochondrial ROS and is associated with an increase in PTEN‐induced kinase 1 (PINK1) and Parkin. Mitochondrial recruitment of PINK1 was determined to be Akt‐dependent, as knockdown of Akt reduced PINK1 mitochondrial localization. Akt did not modulate mitochondrial dysfunction by altering membrane depolarization; however, macrophages exposed to chrysotile asbestos had a decrease in mitochondrial membrane potential in a time‐dependent manner. Akt enhanced macrophage survival and induced autophagosome formation by an induction of LC3 expression. Biological evidence to support this shows that Akt deficient mice have reduced mitochondrial localized PINK1 and Parkin expression, decreased macrophage survival, and are protected from pulmonary fibrosis compared to WT mice. Moreover, alveolar macrophages obtained from asbestosis and idiopathic pulmonary fibrosis patients had increased cell survival and increased mitochondrial localization of PINK1 and Parkin. These observations suggest a direct link between Akt activation, mitophagy, and pulmonary fibrosis by regulating mitochondrial dynamics. 2R01ES015981‐07 & BX001135‐01