Metal mechanisms of mitochondrial toxicity: recent review of arsenic, cadmium, and lead-induced nephrotoxicity.

The kidney is rich in mitochondria that are vulnerable to toxic metal injury during the filtration, secretion, and reabsorption processes required for the excretion of wastes, solutes, and xenobiotics. Understanding the mechanisms of mitochondrial toxicity of metals can provide critical insights into the mitochondrial etiology of kidney damage and the susceptible nephron segments. Recent research has revealed potential new mechanisms of mitochondrial toxicity and related adverse bioenergetic effects due to metal and metalloid exposure. Here we reviewed 20 studies on the mitotoxic effects from exposure to arsenic (n = 6), cadmium (n = 10), and lead (n = 3) as individual toxicants and as mixtures (n = 1) to gain insights into mitochondrial mechanisms of nephrotoxicity and to identify current research gaps. Studies have shown that exposure to toxic metals is associated with adverse kidney health and function with underlying changes in gene expression and enzymatic activity, loss of mitochondrial membrane potential, cellular oxidative imbalance, and inhibited electron transport. The mechanisms of damage and the severity of injury were metal and dose dependent. The proximal tubule was the most prevalent target segment of the nephron for metal-induced mitochondrial toxicity, specifically to cadmium exposure as an individual toxicant and as part of a mixture. There is a clear need to understand metal-induced mitochondrial nephrotoxicity and key research gaps that need to be filled, including the need for sex-specific and time-series studies.