Mitochondria–RNA Binding Protein Crosstalk in Neurodegeneration: Mechanisms Linking Mitochondrial Stress, RNA Dysregulation and Neuronal Vulnerability

Abstract Mitochondria have long been organelles, recognized as bioenergetic organelles. Additionally, mitochondria have recently emerged as central hubs of RNA regulatory networks. A growing body of evidence demonstrates that mitochondria and RNA-binding proteins (RBPs) engage in a two-way dialogue to integrate stress responses, proteostasis, and adaptive cellular programs. Several RBPs linked to neurodegenerative diseases, such as TDP-43, FUS, TIA-1, TIAR, and Pumilio family proteins, directly impact mitochondrial biogenesis, fusion–fission dynamics, and mitophagy. In turn, mitochondrial signaling can reprogram RBP behavior via post-translational modification, recruitment to mitochondrial membranes, and stress-induced translocation to cytoplasmic ribonucleoprotein granules. Interference with this regulatory axis significantly impacts on neuronal homeostasis. Mislocalization of RBPs is often linked to mitochondrial fragmentation, compromised oxidative phosphorylation, decreased ATP production, and increased reactive oxygen species (ROS) production. Notably, mitochondrial dysfunction is a common early event, even before apparent neuron loss, in several neurodegenerative diseases. Emerging data also points to a role for the mitochondria RBP interface in selective neuronal vulnerability, particularly in motor neurons that rely heavily on both mitochondrial bioenergetics and highly regulated RNA metabolism. Here, we review recent work that has helped define the molecular underpinnings of mitochondrial RBP crosstalk, discussing emerging tools that have facilitated these findings (including super-resolution microscopy, RNA interactome mapping, and mitochondrial proteomics), while highlighting therapeutic approaches that seek to restore mitochondrial and RNA homeostasis. Understanding the interface between mitochondria and RBPs provides a novel paradigm for neurodegeneration and may open new therapeutic opportunities. Graphical Abstract Mitochondria and RNA-binding proteins (RBPs) establish a bidirectional regulatory axis that links cellular metabolism with stress-responsive RNA processing and proteostasis. The interruption of this crosstalk triggers a self-perpetuating pathogenic cycle marked by mitochondrial fragmentation, compromised oxidative phosphorylation, and increased reactive oxygen species, which subsequently leads to the mislocalization and aggregation of RBPs. These defects result in extensive RNA dysregulation and proteostatic failure, ultimately undermining neuronal homeostasis and facilitating neurodegenerative pathology.