Mitochondria at the intersections of RNA modifications and metabolism reprogramming implications in cell death, tumor microenvironment, and immunotherapy

Abstract

Mitochondria, the powerhouse of the cell, orchestrate a plethora of critical functions, including energy production, metabolic regulation, programmed cell death, and signal transduction. Their pivotal role in the pathogenesis of numerous diseases underscores their significance. Among the various regulatory mechanisms, RNA modifications emerge as a dominant posttranscriptional modulator of gene expression, increasingly recognized for their profound impact on mitochondrial functions. Groundbreaking discoveries have unveiled compelling links between RNA modifications and oxidative phosphorylation, regulated cell death-particularly cuproptosis-and antitumor immunity, underscoring RNA modifications' vital role and untapped potential in mitochondrial biology, cancers and aging-related diseases. In this Review, we comprehensively catalog the primary RNA modifications modifiers and their small-molecule inhibitors that influence mitochondrial functions. We explore the latest research delineating RNA modifications' involvement in mitochondria-related glucose metabolism, regulated cell death, and mitochondrial dynamics, presenting an intricate regulatory network. Furthermore, we investigate the intriguing intersection of RNA modifications and mitochondria-related antitumor immunity, highlighting prospective therapeutic targets to enhance immunotherapy outcomes. This review not only accentuates the critical importance of RNA modifications in mitochondrial function but also paves the way for novel therapeutic strategies in disease treatment.

Keywords: Aging-related disease; Cancer; Drug resistance; Glucose metabolism; Mitochondria; Mitochondrial dynamics; RNA modifications; Regulated cell death; Tumor microenvironment.

Fig. 1

The role of mitochondria-related RNA modifications in cancer and non-cancer diseases. Disease-promoting (red) and disease-inhibiting (blue) roles of RNA modifications on downstream targets, including coding and non-coding RNAs, are listed for different cancer types (grey) and non-cancer diseases (blue). The associated genes are categorized on the basis of mitochondrial functions (glucose metabolism, regulated cell death and mitochondrial dynamics). RNA modifications modifiers are listed at the outer column, including writers (purple), readers (green) and erasers (yellow). GBMLGG: Low Grade Glioma and Glioblastoma, HNSC: Head and Neck cancer, THCA: Thyroid Cancer, LUAD: Lung Adenocarcinoma, LIHC: Liver Hepatocellular Carcinoma, AKI: Acute Kidney Injury, PAAD: Pancreatic Adenocarcinoma, PRAD: Prostate Adenocarcinoma, BLCA: Bladder Urothelial Carcinoma, ESCA: Esophageal Carcinoma, AML: Acute Myeloid Leukemia, BRCA: Breast Invasive Carcinoma, STAD: Stomach Adenocarcinoma, COADREAD: Colon Adenocarcinoma and Rectum Adenocarcinoma, CESC: Cervical Squamous Cell Carcinoma

Fig. 2

Hallmark findings of mitochondria-related RNA modifications. The hallmark findings are categorized on the basis of mitochondrial functions (glucose metabolism—green area, regulated cell death—yellow area and mitochondrial dynamics—red area) and into 3 levels (mitochondrial biology—inner circle, cell biology—median circle and antitumor immunology—outer circle)

Fig. 3

RNA modifications in mitochondria-related glucose metabolism. Glucose is metabolized via glycolysis in the cytosol (green area), TCA cycle and OXPHOS in mitochondria (red area). The Hippo, Wnt and HIF-1α pathways regulate the expression levels of enzymes that participate in glycolysis. RNA modifications in mitochondria-related glucose metabolism is implemented by RNA modifications modifiers, including writers in red, readers in blue and erasers in yellow

Fig. 4

RNA modifications in mitochondria-related cell death. a Acetyl-CoA generated from the TCA cycle in the mitochondrial matrix is converted into PUFA-PL. Together with the ROS generated throughout the ETC on the IMM and Fe²⁺, PUFA-PLs are prone to oxidize into PL-PUFA-OOH that leads to cellular and mitochondrial lipid peroxidation, thus inducing ferroptosis. The GPX4 pathway acts as an anti-ferroptotic mediator. b The NLRP3 inflammasome activated by ROS induces caspase 1 activation and leads to the cleavage of IL-1β, IL-18 and GSDMD. N-GSDMDs form GSDMD pores that permeabilize the plasma membrane, leading to pyroptosis. c The intrinsic stimulus activates the BAX/BAK protein and induces MOMP, which leads to leakage of cytochrome C from the IMM. Cytochrome C activates the apoptosome, followed by caspase 3/7 activation, leading to apoptotic cell death. d Mitochondrial Cu(I), either from Cu(II) transported by DSF/ES or through SLC31A1, binds to FDX1 and lipoyled DLAT, destabilizing the Fe-S complex in IMS as well as DLAT oligomerization, leading to cuproptosis. The RNA modifications modifiers that regulate the key molecules involved in mitochondria-related cell death include writers in red, readers in blue and erasers in yellow. PUFA-PL polyunsaturated fatty acid-containing phospholipids, IMM inner mitochondrial membrane, IMS mitochondrial intermembrane space, GPX4 glutathione peroxidase, MOMP mitochondrial outer membrane permeabilization, DSF disulfiram, ES elesclomol, FDX1 ferredoxin 1, DLAT dihydrolipoyl transacetylase, LA lipoic acid

Fig. 5

RNA modifications in mitochondrial dynamics. a Mitophagy is mainly composed of 4 processes: depolarization of mitochondria, formation of mitochondrial autophagosomes, fusion of mitochondrial autophagosomes and lysosomes, and degradation by lysosomes. The formation of mitochondrial autophagosomes are triggered by the PINK1-Parkin pathway and receptor-mediated pathway. b Mitochondrial fission is significantly mediated by DRP1. Mitochondrial fusion is triggered by OPA1 and MFN1/2. RNA modifiers that regulate the key molecules involved in mitochondrial dynamics include writers (red), readers (blue) and erasers (yellow). PINK1 PTEN-induced kinase 1, DRP1 GTPase enzyme dynamin-related protein 1, OPA1 optic atrophy protein 1, MFN 1/2 mitofusin 1/2

Fig. 6

RNA modifications in the regulation of mitochondria-related tumor microenvironment. Mitochondria-related glucose metabolism, regulated cell death and mitochondrial dynamics are significantly correlated with the dynamic changes of the TME and tumor immune response. The role of RNA modifications in the regulation of the TME has not been discussed, yet it can be hypothesized and deduced. RNA modifiers that regulate the key molecules of mitochondria-related TME include writers (red), readers (blue) and erasers (yellow). TME tumor microenvironment

Fig. 7

Overview of mitochondrial functions and their links with RNA modifications. Mitochondria play a crucial role in glucose metabolism, apoptosis, ferroptosis, necroptosis, pyroptosis, cuproptosis, mitophagy, mitochondrial fission and fusion and the tumor immune response. The key molecules involved in mitochondrial functions, which are reported to be associated with RNA modifications are depicted in color, whereas other molecules are in gray