RNA-Binding Proteins Implicated in Mitochondrial Damage and Mitophagy.

The mitochondrial lifecycle comprises biogenesis, fusion and cristae remodeling, fission, and breakdown by the autophagosome. This cycle is essential for maintaining proper cellular function, and inhibition of any of these processes results in deterioration of bioenergetics and swift induction of apoptosis, particularly in energy-craving cells such as myocytes and neurons. Regulation of gene expression is a fundamental step in maintaining mitochondrial plasticity, mediated by (1) transcription factors that control the expression of mitochondrial mRNAs and (2) RNA-binding proteins (RBPs) that regulate mRNA splicing, stability, targeting to mitochondria, and translation. More recently, RBPs have been also shown to interact with proteins modulating the mitochondrial lifecycle. Importantly, misexpression or mutations in RBPs give rise to mitochondrial dysfunctions, and there is strong evidence to support that these mitochondrial impairments occur early in disease development, constituting leading causes of pathogenesis. This review presents key aspects of the molecular network of the disease-relevant RBPs, including transactive response DNA-binding protein 43 (TDP43), fused in sarcoma (FUS), T-cell intracellular antigen 1 (TIA1), TIA-related protein (TIAR), and pumilio (PUM) that drive mitochondrial dysfunction in the nervous system.