Journal article
Ammonia sensitive SLC4A11 mitochondrial uncoupling reduces glutamine induced oxidative stress
Redox biology, Vol.26, p.101260
09/01/2019
DOI: 10.1016/j.redox.2019.101260
PMCID: PMC6604051
PMID: 31254733
Abstract
SLC4A11 is a NH3 sensitive membrane transporter with H+ channel-like properties that facilitates Glutamine catabolism in Human and Mouse corneal endothelium (CE). Loss of SLC4A11 activity induces oxidative stress and cell death, resulting in Congenital Hereditary Endothelial Dystrophy (CHED) with corneal edema and vision loss. However, the mechanism by which SLC4A11 prevents ROS production and protects CE is unknown. Here we demonstrate that SLC4A11 is localized to the inner mitochondrial membrane of CE and SLC4A11 transfected PS120 fibroblasts, where it acts as an NH3-sensitive mitochondrial uncoupler that enhances glutamine-dependent oxygen consumption, electron transport chain activity, and ATP levels by suppressing damaging Reactive Oxygen Species (ROS) production. In the presence of glutamine, Slc4a11(-/-) (KO) mouse CE generate significantly greater mitochondrial superoxide, a greater proportion of damaged depolarized mitochondria, and more apoptotic cells than WT. KO CE can be rescued by MitoQ, reducing NH3 production by GLS1 inhibition or dimethyl alpha Ketoglutarate supplementation, or by BAM15 mitochondrial uncoupling. Slc4a11 KO mouse corneal edema can be partially reversed by aKetoglutarate eye drops. Moreover, we demonstrate that this role for SLC4A11 is not specific to CE cells, as SLC4A11 knockdown in glutamine-addicted colon carcinoma cells reduced glutamine catabolism, increased ROS production, and inhibited cell proliferation. Overall, our studies reveal a unique metabolic mechanism that reduces mitochondrial oxidative stress while promoting glutamine catabolism.
Details
- Title: Subtitle
- Ammonia sensitive SLC4A11 mitochondrial uncoupling reduces glutamine induced oxidative stress
- Creators
- Diego G. Ogando - Indiana University BloomingtonMoonjung Choi - Indiana University BloomingtonRajalekshmy Shyam - Indiana University BloomingtonShimin Li - Indiana University BloomingtonJoseph A. Bonanno - Indiana University Bloomington
- Resource Type
- Journal article
- Publication Details
- Redox biology, Vol.26, p.101260
- DOI
- 10.1016/j.redox.2019.101260
- PMID
- 31254733
- PMCID
- PMC6604051
- NLM abbreviation
- Redox Biol
- ISSN
- 2213-2317
- eISSN
- 2213-2317
- Publisher
- Elsevier
- Number of pages
- 14
- Grant note
- TL1 TR002531; UL1 TR002529.gs1 / Indiana University CTSI Postdoctoral Fellow NIH/NCATS CTSI NEI/5R01EY008834 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 09/01/2019
- Academic Unit
- Anatomy and Cell Biology
- Record Identifier
- 9984949240302771
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