Pervasive food contaminant ochratoxin‐A induces energy crisis: Mitochondrial dysfunction in human primary proximal tubule cells

Ochratoxin-A (OTA) is a ubiquitous mycotoxin contaminant in food products and a known nephrotoxin that is not currently regulated in the United States. OTA is hypothesized to be a potential environmental agent causing chronic kidney disease of unknown etiology (CKDu), however the mechanism of OTA toxicity in the human kidney remains elusive. This study aims to elucidate OTA-induced molecular toxicological pathways using primary human proximal tubule epithelial cells (PTECs). We demonstrated that exposure to OTA (10 μM) induces over 7000 differentially expressed genes, including key regulators of mitochondrial fission and fusion. This was confirmed at the cellular level by confocal microscopy, where a breakdown of the mitochondrial network was observed at 100 nM OTA. Crucially, low exposure (10 nM - 1 μM) was found to significantly inhibit basal mitochondrial oxidative phosphorylation as well as glycolysis through measurements of oxygen consumption rate and extracellular acidification, indicating reduced cellular energetics and mitochondrial toxicity. We demonstrate that OTA induces mitochondrial dysfunction and reduced ATP production in PTECs characteristic of renal disease progression. These findings provide insight into early proximal tubule damage induced by OTA which has been linked to pathophysiological changes involved in chronic kidney disease.