Ferritin is regulated by a neuro-intestinal axis in the nematode Caenorhabditis elegans

Abstract

Iron is vital for the life of most organisms. However, when dysregulated, iron can catalyze the formation of oxygen (O2) radicals that can destroy any biological molecule and thus lead to oxidative injury and death. Therefore, iron metabolism must be tightly regulated at all times, as well as coordinated with the metabolism of O2. However, how is this achieved at the whole animal level is not well understood. Here, we explore this question using the nematode Caenorhabditis elegans. Exposure of worms to O2 starvation conditions (i.e. hypoxia) induces a major upregulation in levels of the conserved iron-cage protein ferritin 1 (ftn-1) in the intestine, while exposure to 21% O2 decreases ftn-1 level. This O2-dependent inhibition is mediated by O2-sensing neurons that communicate with the intestine through neurotransmitter and neuropeptide signalling, and requires the activity of hydroxylated HIF-1. By contrast, the induction of ftn-1 in hypoxia appears to be HIF-1-independent. This upregulation provides protection against Pseudomonas aeruginosa bacteria and oxidative injury. Taken together, our studies uncover a neuro-intestine axis that coordinates O2 and iron responses at the whole animal level.

Allele-specific mitochondrial stress induced by Multiple Mitochondrial Dysfunctions Syndrome 1 pathogenic mutations modeled in Caenorhabditis elegans

“…These assessments of SKN-1 activation differ in many ways, but they demonstrate the point that cell-nonautonomous activation could be possible. Furthermore, in C. elegans, metabolic dysfunction in neurons has been documented to activate stress responses in other cells, namely the intestine [94,95]. Such a concept is pertinent given the neurodegenerative nature of MMDS1 and the potential for neuronal dysfunction to impact nonneuronal tissues.…”

Structural and functional relationship of mammalian and nematode ferritins

“…The relationship between ferritin-dependent iron metabolism and O 2 metabolism has been poorly studied. However, there is some evidence indicating the functional relationship between these processes in C. elegans , e.g., ftn-1 gene expression is responsive to changeable oxygen conditions and is significantly upregulated following exposure to 1% O 2 (hypoxia) (Romero-Afrima et al, 2020 ). Few research teams have been trying to identify factors linking iron and O 2 metabolism.…”

“…Additionally, HIF-1 exists in two forms – hydroxylated and non-hydroxylated, and the mechanism of ftn-1 expression regulation depends on these forms (Angeles-Albores et al, 2018 ). The hydroxylated form of HIF-1 inhibits ftn-1 expression under normoxia (Angeles-Albores et al, 2018 ; Romero-Afrima et al, 2020 ).…”

“…The HIF subfamily consists of only one member in C. elegans and four members in mammals (Fong and Takeda, 2008 ). Interestingly, the upregulation of ftn-1 in C. elegans seems to be HIF-1-independent in hypoxia (Romero-Afrima et al 2020 ). Additionally, the expression level of ftn-1 in the intestine is regulated by specific neurons (AQR, URX, and PQR), which use neuropeptide and neurotransmitter signaling that results in decrease in the ftn-1 expression level at 21% O 2 , whereas this effect diminishes at 1% O 2 (Romero-Afrima et al, 2020 ).…”

“…Interestingly, it was observed in C. elegans that under stress conditions such as hypoxia, the upregulated FTN-1 level plays an important role in protection against pathogenic bacteria, e.g., Pseudomonas aeruginosa (PA14). Thus, FTN-1 overexpression may be responsible for the increase in worm resistance to pathogens under abnormal environmental conditions (Ma et al, 2021 ; Romero-Afrima et al, 2020 ).…”