Abstract

Chronic exposure to inorganic arsenic, mainly via drinking water or contaminated food, is a global health problem linked to increased risk of cardiovascular disease, kidney disease, type II diabetes, and certain types of cancer. Among the pathologies associated with prolonged exposure to arsenic is metabolic syndrome, which is defined by a group of risk factors including dyslipidemia, insulin resistance, and inflammation. Two major contributors to metabolic syndrome are mitochondrial dysfunction and increased oxidative stress. One of the main antioxidant defense pathways against oxidative stress is the NRF2 pathway. However, emerging evidence also supports a role for NRF2 in mediating mitochondrial structure and function as well. While the role of NRF2 in metabolic syndrome is controversial, it has been shown that KEAP1-knockdown (KEAP1-KD) mice, which have constitutively active NRF2, fed a high fat diet, exhibit increased markers of metabolic syndrome, thus inferring prolonged activation of NRF2 could play a key role in driving this syndrome. Previously, our group has shown that arsenic inhibits autophagy, resulting in the prolonged activation of NRF2. Here, we show that arsenic-induced activation of NRF2, or constitutive activation of NRF2 in KEAP1 knockout cells, results in fragmentation of the mitochondrial network. Interestingly, NRF2 knockout cells have fused mitochondria that are resistant to arsenic-induced fragmentation, indicating NRF2 may regulate changes to the mitochondrial network during stress. Arsenic treatment also prevents the mitophagic removal of fragmented mitochondria. Furthermore, pretreatment with rapamycin, an autophagy activator, prevented arsenic-mediated autophagy inhibition, and restored NRF2 to basal levels. These findings indicate that NRF2 levels can directly affect the mitochondrial network, which could play a key role in mediating mitochondrial function and cellular metabolism during prolonged exposure to arsenic. Furthermore, pharmacological activation of the autophagy pathway to restore NRF2 homeostasis, or pharmacological inhibition of mitochondrial fission could be viable therapeutic strategies to treat metabolic syndrome.

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