Ten key PTMs, including lactylation, succinylation, 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) are summarized to provide a comprehensive resource for understanding mitochondrial plasticity in health and disease.
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.
Current understanding of PINK1-Parkin-dependent and independent mitophagy pathways are summarized, highlighting mechanistic distinctions and coordinated regulation, as well as the expanding therapeutic potential of targeting mitophagy in disease.
S. Martens, Ian G. Ganley· Nature reviews. Molecular ce...· 0 citations
Emerging insights into PTM-mediated regulation of MAVS are summarized and broader implications for mitochondrial antiviral signaling are outlined, highlighting new avenues for therapeutic modulation of innate immunity and cell fate during viral infection.
Nao Morimoto, Tomohiko Okazaki· Frontiers in Physiology· 0 citations
Mitochondrial quality control (QC) comprises interconnected pathways that preserve organelle function by detecting damage and mediating repair, remodelling, or elimination of defective components. Although many sub-organellar QC mechanisms are well characterised, stress is often sensed first at the level of mitochondrial function rather than at individual molecular targets. Functional domains such as oxidative folding, bioenergetics, redox balance, pH, and thermogenesis act as sensory portals that detect perturbations and trigger adaptive reprogramming of mitochondrial activity. In this perspective, we provide a conceptual perspective for mitochondrial QC as a mechanistically integrated network, emphasising how changes in these functional states couple diverse QC modules—including proteases, antioxidant systems, mitochondrial dynamics, mitophagy, and mitochondrial-derived vesicles—into a unified surveillance system. We propose that primary stressors, such as redox imbalance, are progressively converted into secondary stress signals, including reactive oxygen species accumulation, membrane depolarisation, metabolite redistribution, and altered lipid or nucleic-acid structure. These secondary signals propagate across mitochondrial and cytosolic compartments, amplifying QC by coordinating the engagement of repair, remodelling, and organelle-elimination pathways. This cascading transformation of stress signals not only limits the impact of the initial insult but also enhances adaptive capacity by driving synergistic deployment of QC processes across multiple mechanistic layers.
Fulya Ozcan, Filip Vujovic, Ramin M. Farahani· Biomolecules· 1 citation
More research in the field may unravel the mechanistic details of the organellar crosstalk that works in concert with classical aging pathways to sustain aging progression, which may help promote healthier aging.
Initially characterized as an epigenetic marker for transcriptional regulation, lysine lactylation is now recognized as a pervasive posttranslational modification with extensive functions beyond those associated with chromatin. Recent methodological advances in the resolution of stereoisomeric dynamics have established L-lactylation as the predominant glycolysis-derived functional form, providing a metabolic switch that couples glycolytic flux to oncogenic signaling. Here, we provide a comprehensive overview of non-histone L-lactylation in cancer biology. We define the spatially compartmentalized catalytic network governing this process, detailing how nuclear EP300/CBP, cytosolic AARS1, and mitochondrial AARS2 mediate stereospecific targeted modifications. At the molecular level, non-histone L-lactylation alters protein biophysics via charge neutralization, steric hindrance, and interface remodeling. These physicochemical alterations govern fundamental enzymatic kinetics, complex assembly, subcellular trafficking, and proteasomal degradation processes. Through primarily transcription-independent mechanisms, L-lactylation enables cancer cells to sustain metabolic flexibility, promote the repair of damaged DNA, and foster an immunosuppressive tumor microenvironment. Because tumors exploit these regulatory networks to drive adaptive resistance across diverse therapeutic modalities, we examine current strategies for pharmacological intervention. Finally, we highlight critical unresolved questions in this field. Notably, the identification of lactylation-specific readers and the development of stereoisomer-resolved chemobiological tools will be essential to fully leverage this metabolism–modification axis for cancer therapy.
Ying-Ying Guo, Lanyang Gao, Shundan Li et al.· Molecular Cancer· 0 citations
Metabolic reprogramming and the evasion of regulated cell death are two canonical hallmarks of cancer, yet the mechanistic threads connecting these distinct biological phenomena remain incompletely understood. The “Warburg effect,” characterized by robust aerobic glycolysis, results in the massive accumulation of lactate. Once dismissed as a metabolic waste product, lactate has recently emerged as a pivotal signaling molecule and an epigenetic precursor for lysine lactylation (Kla), a novel post-translational modification that fundamentally reshapes the chromatin landscape. Concurrently, ferroptosis—an iron-dependent form of non-apoptotic cell death driven by unrestrained lipid peroxidation—has garnered intense interest as a therapeutic vulnerability in therapy-resistant tumors. However, a paradoxical observation persists highly glycolytic tumors, despite generating abundant ROS (reactive oxygen species), often display intrinsic resistance to ferroptosis. In this review, we propose that histone and non-histone lactylation serves as the critical “epigenetic bridge” coupling metabolic flux to ferroptosis evasion. We dissect the molecular machinery by which the “Lactate–Kla axis” transcriptionally activates antioxidant defenses (e.g., GPX4, SLC7A11) and remodels the tumor microenvironment to suppress ferroptotic triggers. Furthermore, we delineate how targeting the writers and erasers of lactylation can dismantle this metabolic shield, offering a rational strategy to re-sensitize refractory tumors to ferroptosis-inducing therapies. This synthesis highlights a new frontier in cancer biology where metabolism, epigenetics, and cell fate decisions converge.
Yali Liu, Qiang Yang, Xiaoqiang Wang et al.· Redox Biology· 1 citation
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