Mitochondria are dynamic systems adapted to the different cellular demands. In this context, it is hypothesized that lipids, and particularly fatty acids, are also affected by these adaptations and supported at transcriptional level. By analyzing seven mammalian organs from rats, covering the three germ layers and belonging to the four basic types of tissue, we evaluated the differences in the lipidome's fatty acid profiles, calculated fatty acid-derived parameters including susceptibility to lipid peroxidation, and estimated enzymatic activity. Then, we analyzed gene expression datasets of rat tissues to identify specific signatures supporting fatty acid profiles and extended the analysis to human datasets to evaluate shared and differential traits. Our findings demonstrate that a) mitochondrial lipotype is determined by the basic type of tissue instead of the germ layer origin; b) mitochondrial fatty acid profiles define the tissue; c) myristic acid (FA14:0) and docosapentaenoic acid n-6 (22:5n-6) act as biomarkers for global definition of the tissue mitotype; d) brain and adipose tissue mitochondria are especially resistant to lipid peroxidation; e) mitochondrial fatty acid signatures are supported at transcriptional level; and f) tissue-specific transcriptomic patterns of elongase and desaturase expression in rats are largely conserved in humans (e.g., Elovl4, Elovl7, Scd, and Fads6), although species-specific differences are observed for certain transcripts, such as Elovl2, Elovl3, and Elovl5. Our findings suggest that mitochondria share general inter-tissue features but also exhibit tissue-specific specializations in their lipid phenotype. We infer that the mitochondrial fatty acid composition and its derived peroxidation index may be programmed, tissue-specific traits.

Se is essential for central nervous system function, and its deficiency is strongly associated with cognitive decline, especially in neurodegenerative disorders such as Alzheimer's disease (AD). Although Se exerts its effects through selenoproteins, the molecular basis of its neuroprotective action remains unclear. Among selenoproteins, the endoplasmic reticulum (ER)-resident selenoprotein K (SELENOK) is closely linked to cognitive function and therapeutic potential in AD. Here, we examined how SELENOK regulates synaptic plasticity and contributes to Se-mediated neuroprotection in AD. Using age-gradient SELENOK knockout models and palmitoyl-proteomics, we identified GluA2 (formerly GluR2) as a key downstream target. Mechanistically, SELENOK enhanced the activity of DHHC6, an ER-localized palmitoyltransferase, to promote GluA2 palmitoylation, facilitating its ER retention and efficient assembly of AMPA-type glutamate receptors (AMPARs). Notably, GluA2 palmitoylation was reduced in both AD model mice and postmortem brains of patients with AD. Importantly, neuronal overexpression of SELENOK in the hippocampus restored synaptic plasticity and cognitive function in AD mice. Overall, this study uncovers a novel SELENOK-dependent mechanism regulating AMPAR assembly, offering experimental support for developing Se-based therapeutic strategies for AD.

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders characterized by impairments in social communication, restricted interests, and repetitive behaviors. Although its etiology remains incompletely understood, increasing evidence suggests a multifactorial origin involving genetic alterations, immune dysregulation, and environmental exposures. The aim of this study was to investigate the redox-sensitive Nrf2 signaling pathway in primary dermal fibroblasts isolated from ASD patients. Our results revealed constitutive activation of Nrf2, accompanied by reduced expression of its downstream target heme oxygenase-1 (HO1) and marked nuclear accumulation of the transcriptional repressor BACH1 in ASD cells. Moreover, ASD fibroblasts failed to increase Nrf2 nuclear translocation upon sulforaphane (SFN) stimulation, a response consistent with elevated basal levels of Keap1, a negative regulator that sequesters Nrf2 in the cytoplasm. Notably, treatment with hemin, known to induce nuclear export and degradation of BACH1, successfully restored HO1 gene and protein expression and ameliorated impaired mitochondrial function in ASD fibroblasts, as suggested by the decrease of mtROS levels and the restored mitochondrial membrane potential. Collectively, these results identify a dysregulation of the Nrf2-Keap1-BACH1 axis in ASD and suggest that pharmacological targeting of this pathway may offer therapeutic potential to correct the redox imbalance associated with the disorder.

Renal ischemia-reperfusion injury (RIRI), a major contributor to acute kidney injury (AKI) and delayed graft function (DGF), is closely associated with dysregulation of metal ion homeostasis. Although copper and iron metabolism exhibit interconnected regulatory pathways, the temporal dynamics and functional interplay of these metal ions in RIRI pathogenesis remain poorly understood. Our study demonstrates that cuproptosis and ferroptosis, two distinct forms of cell death induced by metal ion overload, occur simultaneously within 6 h after reperfusion. Notably, ischemia-reperfusion injury induced iron overload significantly sensitizes renal tubular cells to copper-mediated cytotoxicity. Mechanistic investigations demonstrate that hypoxia-reoxygenation triggers Fe (II) accumulation, which subsequently downregulates [4Fe–4S] cluster assembly proteins. This impairment directly compromises the structural integrity of the cuproptosis-regulating protein LIAS by inducing [4Fe–4S] cluster loss, ultimately leading to defective protein lipoylation that drives cuproptosis progression. Crucially, these pathological effects can be attenuated through either overexpression of [4Fe–4S] cluster assembly machinery or therapeutic application of iron-chelating agents. Our findings establish a novel iron-copper crosstalk mechanism in RIRI pathophysiology and propose targeted strategies focusing on [4Fe–4S] cluster homeostasis and iron chelation for clinical intervention.