Current insights into the implications of m6A RNA methylation and autophagy interaction in human diseases

Abstract

Autophagy is a conserved degradation process crucial to maintaining the primary function of cellular and organismal metabolism. Impaired autophagy could develop numerous diseases, including cancer, cardiomyopathy, neurodegenerative disorders, and aging. N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic cells, and the fate of m6A modified transcripts is controlled by m6A RNA binding proteins. m6A modification influences mRNA alternative splicing, stability, translation, and subcellular localization. Intriguingly, recent studies show that m6A RNA methylation could alter the expression of essential autophagy-related (ATG) genes and influence the autophagy function. Thus, both m6A modification and autophagy could play a crucial role in the onset and progression of various human diseases. In this review, we summarize the latest studies describing the impact of m6A modification in autophagy regulation and discuss the role of m6A modification-autophagy axis in different human diseases, including obesity, heart disease, azoospermatism or oligospermatism, intervertebral disc degeneration, and cancer. The comprehensive understanding of the m6A modification and autophagy interplay may help in interpreting their impact on human diseases and may aid in devising future therapeutic strategies.

5-Azacytidine Inhibits the Activation of Senescence Program and Promotes Cytotoxic Autophagy during Trdmt1-Mediated Oxidative Stress Response in Insulinoma β-TC-6 Cells

“…Decreased m 6 A signals were also associated with autophagy induction in our experimental setting, namely 5-azaC post-treatment resulted in diminished pools of m 6 A and elevated levels of LC3B compared to HP stimulation ( Figure 5 C and Figure 6 B). M 6 A RNA modification can also modulate autophagy-mediated anticancer drug resistance [ 50 , 51 ]. Depletion of METTL3, a primary m 6 A methyltransferase, promoted sorafenib resistance in hepatocellular carcinoma (HCC) cells and activated autophagy-associated pathways by limited stability of FOXO3 mRNA under hypoxic conditions [ 52 ].…”

LKB1 Regulates Vascular Macrophage Functions in Atherosclerosis

“…Macrophage autophagy seems to have a dual role in atherosclerosis: dysregulated autophagy promotes atherosclerosis, and moderate autophagy inhibits plaque progression ( Zahid et al, 2021 ). Autophagy is a conservative degradation mode of cells, which is essential for maintaining the main functions of cell metabolism ( Chen et al, 2021 ). When cells suffer from nutrient deficiency, oxidative stress, and organelle dysfunction, autophagy degrades unwanted materials through a lysosomal-dependent pathway to maintain cell homeostasis ( Duan et al, 2020 ).…”

Role of m6A Methylation in the Occurrence and Development of Heart Failure

“…In mammalian cells, autophagy currently known includes at least three different pathways: macro-autophagy, micro-autophagy and chaperone mediated autophagy (CMA) (94,95). Among them, the difference among the three mainly lies in the process of binding with lysosomes: macro-autophagy is that cytoplasmic components are directly attached to lysosomes and then directly degraded by lysosomal hydrolases; Micro-autophagy is the invagination of lysosomal membrane, which is engulfed by lysosomes after forming vesicles; CMA enters the lysosome through lysosomal associated membrane protein 2A (LAMP-2A) receptor in the form of complex with the help of chaperone proteins such as Hsc-70 (96,97).…”

“…M6A methylation can affect the expression of autophagy related genes, regulate autophagy, and play an important role in the occurrence and development of heart failure (97,111,112). It is reported that m6A methylation can inhibit autophagy by affecting the post transcriptional regulation of autophagy related gene 1 (ATG1)/Unc-51-like kinase 1 (ULK1) (113).…”