More than a duologue: In-depth insights into epitranscriptomics and ferroptosis

Abstract

Beyond transcription, RNA molecules are enzymatically modified to influence the biological functions of living organisms. The term "epitranscriptomics" describes the changes in RNA strands aside from altering the innate sequences. Modifications on adenosine (A) are the most widely characterized epitranscriptomic modification, including N⁶-methyladenosine (m⁶A), N¹-methyladenosine (m¹A), polyadenylation, and adenosine-to-inosine (A-to-I) RNA editing, and modifications on other nucleotides seem to be fewer, such as N⁷-methylguanosine (m⁷G), 5-methylcytosine (m⁵C), and pseudouridine (Ψ). These changes on the RNA strand surface, exclusively by their RNA-modifying proteins (RMPs), are reported in various biological phenomena, including programmed cell death (PCD). One necro-biological phenomenon that has been observed for long but has started to gain heed in recent years is "ferroptosis." The phospholipid peroxidation by polyunsaturated-fatty-acid-containing-phospholipid hydroperoxyl (PLOOH) radicals destroys membrane integrity due to a series of mechanisms. The Fenton reaction, constituting the final Haber-Weiss reaction that is less recognized, collaboratively leading to the conversion of polyunsaturated fatty acid (PUFA) to PLOOH, is the etymological origin of ferroptosis. However, it is with increasing evidence that ferroptotic signaling is also intervened by epitranscriptomic modifications, although the truth is still ambiguous. We attempted to delineate some up-to-date discoveries on both epitranscriptomics and ferroptosis, bringing up the fundamentals to address any potential connection between the two. Next, we discussed whether a duologal relationship, or more, exists between the two, taking the ROS level and iron status into consideration. Lastly, we surveyed future perspectives that would favor the understanding of these topics.

Keywords: epitranscriptomics; ferroptosis; iron metabolism; lipid peroxidation; reactive oxygen species.

FIGURE 1

Illustration of RNA-modifying proteins on mRNA and common RNA modifications. Common base modifications include N⁶–methyladenosine (m⁶A), N¹–methyladenosine (m¹A), pseudouridine (ψ), and 5–methycytosine (m⁵C), to name but a few. Less common modifications are also listed in the illustration. RNA-modifying proteins that govern the expression of the mRNA transcript by manipulating epitranscriptomic sites include (1) writers that deposit RNA modifications, (2) erasers that remove the epitranscriptomics modifications, and (3) readers that are recruited and recognize the modifications to alter the fate of transcripts. Reprinted from “Common eukaryotic mRNA modifications”, by BioRender.com (2020). Retrieved from https://app.biorender.com/biorender-templates.

FIGURE 2

Pathways of ferroptosis. The entirety of ferroptosis signaling is complex and orchestrated by different sub-pathways, along with a multitude of regulatory proteins or substances. The antioxidant system starts with system xc⁻ activity that assists the exchange of cystine and glutamate. Intracellular cystine is converted, in multi-step reactions, to GSH. The transsulfuration reaction starts with conversion of intracellular methionine to cysteine and joins the antioxidant system to enhance GSH production. Lipid ROS production from membrane PUFAs, intracellular lipid droplets, and acetyl-CoA resulted from mitochondrial aerobic respiration, which is negatively regulated by lipophagy, provides predominant lipid source to produce lipid ROS by joining the Fenton/Haber–Weiss reaction. Iron metabolism starts with Fe³⁺ endocytosis initiated by a transferrin receptor, and STEAP3-mediated reduction to Fe²⁺ takes place in endosome. Fe²⁺ joins LIP by FTH1/FTL. Ferritinophagy triggers the release of Fe²⁺ to join intracellular ROS pool and proceeds to the Fenton/Haber–Weiss reaction to produce lipid ROS. Taken together, the PUFA-PLOOH resulting from the reactions induces ferroptotic damage with the mechanism that lacks exactitude. Created with BioRender.com.

FIGURE 3

Fenton/Haber–Weiss reaction. Created with BioRender.com.