Redox dysregulation, an imbalance between oxidants and antioxidants, is crucial in the pathogenesis of various neurodegenerative diseases. Within this context, the “redoxome” encompasses the network of redox molecules collaborating to maintain cellular redox balance and signaling. Among these, cysteine-sensitive proteins are fundamental for this homeostasis. Due to their reactive thiol groups, cysteine (Cys) residues are particularly susceptible to oxidative post-translational modifications (PTMs) induced by free radicals (reactive oxygen, nitrogen, and sulfur species) which profoundly affect protein functions. Cys-PTMs, forming what is referred to as “cysteinet” in the redox proteome, are essential for redox signaling in both physiological and pathological conditions, including neurodegeneration. Such modifications significantly influence protein misfolding and aggregation, key hallmarks of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and notably, amyotrophic lateral sclerosis (ALS). This review aims to explore the complex landscape of cysteine PTMs in the cellular redox environment, elucidating their impact on neurodegeneration at protein level. By investigating specific cysteine-sensitive proteins and the regulatory networks involved, particular emphasis is placed on the link between redox dysregulation and ALS, highlighting this pathology as a prime example of a neurodegenerative disease wherein such redox dysregulation is a distinct hallmark.

The introduction of new sequencing approaches into clinical practice has radically changed the diagnostic approach to mitochondrial diseases, significantly improving the molecular definition rate in this group of neurogenetic disorders. At the same time, there have been no equal successes in the area of in-depth understanding of disease mechanisms and few innovative therapeutic approaches have been proposed recently. In this regard, the identification of the molecular basis of phenotypic variability in primary mitochondrial disorders represents a key aspect for deciphering disease mechanisms with important therapeutic implications. In this study, we present data from proteomic investigations in two subjects affected by mitochondrial disease characterized by a different clinical severity and associated with the same variant in the TWNK gene, encoding the mitochondrial DNA and RNA helicase with a specific role in the mtDNA replisome. Heterozygous pathogenic variants in this gene are associated with progressive external ophthalmoplegia and ptosis, usually with adult onset. The overall results suggest an imbalance in glucose metabolism and ROS production/regulation, with possible consequences on the phenotypic manifestations of the enrolled subjects. Although the data will need to be validated in a large cohort, proteomic investigations have proven to be a valid approach for a deep understanding of these neurometabolic disorders.

Advances in next-generation sequencing have significantly improved the molecular diagnosis of mitochondrial diseases (MDs), a group of heterogeneous neurogenetic disorders. However, progress in understanding their pathogenic mechanisms and translating this knowledge into effective therapies remains limited. Elucidating the molecular determinants of phenotypic variability in primary MDs is essential to uncover disease mechanisms and identify novel therapeutic targets. We investigated a cohort of eight adult patients with genetically confirmed Progressive External Ophthalmoplegia (PEO)—an extremely rare mitochondrial disorder—and compared them with eight age- and sex-matched healthy controls. A comprehensive multi-omics approach combining LC–MS/MS-based proteomics, UPLC–MS/MS-based metabolomics, ATR–FTIR spectroscopy, and chemometric multivariate analysis was employed to identify molecular alterations associated with mitochondrial dysfunction. Distinct proteomic and metabolic patterns related to energy metabolism were observed in PEO patients, correlating with their genetic background. Metabolomic analysis showed altered amino acid levels (seven statistically relevant) and disruptions in the metabolism of cysteine, methionine, and glutathione; proteomics finding (154 differentially expressed proteins) revealed dysregulation in extracellular matrix (ECM) organization and immune response pathways. This integrative analytical strategy offers new insights into the molecular complexity of PEO and mitochondrial disorders. The identification of disease-associated molecular signatures may enhance the understanding of pathogenic mechanisms and support the development of improved diagnostic and therapeutic approaches for MDs.

This study explores the chemical composition and biological activities of essential oils (EOs) and hydrolates (Hys) from Origanum heracleoticum (OH), an aromatic plant with known applications in the food industry. While EOs have been widely studied, Hys (co-products of EO distillation) remain largely overlooked. OH was cultivated in the Lucanian and Casola areas, respectively in the regions of Basilicata and Emilia-Romagna, to evaluate the influence of geographic and climatic factors on product composition and activity. Gas chromatographic analysis showed significant variability between the EO and its related Hy. Carvacrol emerged as the dominant compound, ranging from 71% to 91% in both extracts followed by γ-terpinene and thymol in EOs and Hys, respectively. Both EOs and Hys exhibited antimicrobial activity against tested bacterial strains even if active compounds of Hys were relatively more effective than that of EOs. Notably, Lactobacillus rhamnosus (probiotic) showed greater resistance to EOs compared to Escherichia coli (pathogenic), whereas Hys inhibited L. rhamnosus at 25% v/v, while no MIC against E. coli was reached within the tested concentration range (>50% v/v). Interestingly, sub-inhibitory concentrations of Hys (especially those from Lucan area) stimulated L. rhamnosus growth, promoting earlier exponential phase entry and higher final cell densities. Proteomic analysis revealed associated changes in protein secretion, suggesting adaptive metabolic responses. These findings highlight the distinct chemical and biological properties of Hys obtained from a spice widely used in food, and their potential as functional agents. Their ability to influence L. rhamnosus growth in vitro supports further investigation of their potential microbiota-modulating properties and the development of food supplements and microbiome-friendly formulations.