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.