An exquisite symphony: protein post-translational modifications govern mitochondrial fate

Abstract

Mitochondria are central hubs of metabolic activities in eukaryotic cells and play pivotal roles in various physiological and pathological processes. To accommodate fluctuating metabolic demands and respond to intracellular and extracellular stress, mitochondria undergo highly coordinated fission, fusion, mitophagy, and transport events mediated by dynamics-related proteins. Disrupting this delicate balance impairs mitochondrial bioenergetics and quality control, driving the onset and progression of numerous diseases, including neurodegeneration, heart failure, and cancer. Protein post-translational modifications (PTMs) constitute a critical regulatory layer, conferring remarkable functional diversity upon mitochondrial dynamics proteins beyond their genetic regulation. While extensive studies have characterized canonical PTMs such as phosphorylation and ubiquitination, the intricate roles of a broader spectrum of modifications - particularly those considered “atypical” - in fine-tuning mitochondrial behavior remain underexplored. In this review, we systematically summarize ten key PTMs, including lactylation, succinylation, SUMOylation, and S-nitrosylation, acting on core regulators such as dynamin-related protein 1(DRP1), optic atrophy 1 (OPA1), Parkin, and mitochondrial Rho GTPase 1 (MIRO1). We emphasize how these modifications integrate metabolic cues with mitochondrial dynamics and highlight their potential as diagnostic biomarkers and therapeutic targets. Furthermore, we discuss the sophisticated crosstalk between different PTM types and review emerging protein modification omics and genetic code expansion (GCE) tools designed to dissect the spatiotemporal dynamics of these modifications. By synthesizing current knowledge on these regulatory mechanisms, we aim to provide a comprehensive resource for understanding mitochondrial plasticity in health and disease.