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Inhibition of mitochondrial respiration impairs nutrient consumption and metabolite transport in human retinal pigment epithelium

By Rui Zhang, Abbi L. Engel, Yekai Wang, Bo Li, Weiyong Shen, Mark C Gillies, Jennifer Chao, Jianhai Du

Posted 11 May 2020
bioRxiv DOI: 10.1101/2020.05.11.086827 (published DOI: 10.1021/acs.jproteome.0c00690)

Mitochondrial respiration in mammalian cells not only generates ATP to meet their own energy needs but also couples with biosynthetic pathways to produce metabolites that can be exported to support neighboring cells. However, how defects in mitochondrial respiration influence these biosynthetic and exporting pathways remains poorly understood. Mitochondrial dysfunction in retinal pigment epithelium (RPE) cells is an emerging contributor to the death of their neighboring photoreceptors in degenerative retinal diseases including age-related macular degeneration. In this study, we used targeted-metabolomics and 13C tracing to investigate how inhibition of mitochondrial respiration influences the intracellular and extracellular metabolome. We found inhibition of mitochondrial respiration strikingly influenced both the intracellular and extracellular metabolome in primary RPE cells. Intriguingly, the extracellular metabolic changes sensitively reflected the intracellular changes. These changes included substantially enhanced glucose consumption and lactate production, reduced release of pyruvate, citrate and ketone bodies, and massive accumulation of multiple amino acids and nucleosides. In conclusion, these findings reveal a metabolic signature of nutrient consumption and release in mitochondrial dysfunction in RPE cells. Testing medium metabolites provides a sensitive and noninvasive method to assess mitochondrial function in nutrient utilization and transport. ### Competing Interest Statement The authors have declared no competing interest.

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