Heterocyclic aromatic amines (HAAs) target mitochondrial physiology

Abstract

Heterocyclic aromatic amines (HAA) may be found naturally in plants or are formed through the Maillard reaction when meat is cooked at high temperatures. Previous studies have indicated HAAs are especially toxic to dopaminergic neurons, whereas specific exposures may also affect other neuronal populations such as cholinergic neurons. Biochemical mechanisms of neurotoxic action implicate elevated oxidative stress and afflicted mitochondria. Notably, these mechanisms are of importance in Alzheimers disease (AD) and Parkinsons disease (PD). Most neurodegenerative disease cases are sporadic, where environmental and dietary factors may modulate risk. To further investigate HAA neurotoxicity, we tested the effect of common HAA (harmane, harmine, norharmane, PhIP, and HONH-PhIP) exposure on mitochondrial physiology, a key pathogenic target in AD and PD. Upon assessing mitochondrial bioenergetics, we observed a significant reduction in basal respiration, ATP production, maximal respiratory capacity, and non-mitochondrial respiration, indicating that HAA negatively impacts mitochondrial respiration. Followed by more specific studies on individual mitochondrial complexes, it was found that harmane, harmine, norharmane specifically inhibit complex I enzyme activity, whereas HONH-PhiP, a reactive metabolite of PhIP, inhibits Complex III enzyme activity. Our findings provide significant advancement with respect to underlying mechanisms of toxicity, though also validating HAA exposure as a potential risk factor for AD and PD.

Nuclear DNA and Mitochondrial Damage of the Cooked Meat Carcinogen 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Human Neuroblastoma Cells

“…Our data are in agreement with a previous study, where PhIP (10 μM) induced bioenergetic deficits in SH-SY5Y cells marked by a significant decrease in basal respiration, proton leak, maximal respiration, spare respiration capacity, ATP production, and non-mitochondrial respiratory capacity . Moreover, HONH-PhIP (1–10 μM) induced mitochondrial bioenergetics deficits in primary cortical neurons, marked by decreased basal respiration, ATP production, maximal respiration capacity, and non-mitochondrial respiration . It is noteworthy that our study employed isolated mitochondria incubated with HONH-PhIP and N -acetoxy-PhIP at a single time point at concentrations of 300 nM, which is appreciably greater than daily human PhIP intake.…”

“…29 Moreover, HONH-PhIP (1−10 μM) induced mitochondrial bioenergetics deficits in primary cortical neurons, marked by decreased basal respiration, ATP production, maximal respiration capacity, and non-mitochondrial respiration. 92 It is noteworthy that our study employed isolated mitochondria incubated with HONH-PhIP and Nacetoxy-PhIP at a single time point at concentrations of 300 nM, which is appreciably greater than daily human PhIP intake. Thus, these data serve as the foundation for future studies examining mitochondrial damage in living SH-SY5Y cells exposed chronically to lower dietary-relevant levels of PhIP and HONH-PhIP.…”