ペルオキシソーム病

Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation and is implicated in diverse pathological states1-4. Although mitochondria and other organelles are increasingly being recognized as important modulators of ferroptosis5-7, a unifying mechanism that couples organelle dynamics to ferroptotic execution has remained elusive. Here using quantitative phosphoproteomics, we identified mitochondrial fission factor (MFF) as a key ferroptosis-selective regulator. Mechanistically, the lipid mediator 17-HETE promotes phosphorylation of MFF at Ser155, which triggers the coordinated fragmentation and dysfunction of mitochondria and peroxisomes. This remodelling intensifies interorganelle crosstalk, amplifies oxidative stress and accelerates ferroptotic death. To monitor this phosphorylation event in living cells, we developed MFF-SPARK, a phase-separation-based biosensor, for real-time tracking of ferroptosis through MFF activation. Using MFF-SPARK, we identified PKCβ and DUSP22 as a coordinated kinase-phosphatase pair that governs MFF phosphorylation. We also discovered avermectin B1 as a pharmacological activator of the PKCβ-MFF axis, which can sensitize tumours to ferroptosis in vivo. Together, our findings establish MFF phosphorylation as a central regulatory node in ferroptosis-associated organelle remodelling and provide a conceptual framework and toolbox for monitoring and pharmacologically interrogating ferroptosis.

Mitophagy is increasingly recognized as a context-dependent regulator of cardiac metabolic adaptation rather than solely as a disposal pathway for damaged mitochondria. By coupling mitochondrial turnover to substrate selection, redox control, and inflammatory signaling, mitophagy can influence fatty acid oxidation (FAO), glycolysis, and oxidative phosphorylation (OXPHOS) in cardiomyocytes, vascular endothelial cells, and immune cells. In this review, the term Mitophagy-Metabolic Rewiring Axis (MMRA) is used as an integrative conceptual framework-not as a newly discovered pathway or theory-to organize evidence for bidirectional interactions between mitophagy and metabolic remodeling. The framework comprises stress inputs, mitophagy machinery and flux, metabolic outputs, and cell- or disease-level consequences, while emphasizing that the biological effect of mitophagy depends on cell type, disease stage, and duration of activation. We critically assess the AMP-activated protein kinase (AMPK)-UNC-51-like kinase 1 (ULK1), sirtuin 3 (SIRT3)-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), PTEN-induced kinase 1 (PINK1)-Parkin E3 ubiquitin ligase, and hypoxia-inducible factor 1-alpha (HIF-1α)-BCL2-interacting protein 3 (BNIP3)/FUN14 domain-containing 1 (FUNDC1) modules in atherosclerosis, heart failure, and ischemia/reperfusion injury. Pharmacological, substrate-based, and exercise interventions are evaluated with particular attention to the predominantly preclinical evidence base, methodological limitations in measuring mitophagy flux, and the need for validated human biomarkers. Multi-omics and spatial approaches may improve mechanistic resolution, but clinical translation will require prospective studies that link target engagement to metabolic and cardiovascular outcomes.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with disturbances in arachidonic acid (AA) metabolism; however, the role and regulation of cyclooxygenase-2 (COX-2), a key enzyme in AA metabolism, during disease progression remain incompletely understood. Here, we identify fibroblast growth factor 21 (FGF21) as a previously unrecognized suppressor of hepatic COX-2 in MASLD. Although both FGF21 and COX-2 were elevated in steatotic livers, FGF21 deficiency further augmented hepatic COX-2 expression in mice fed with a high-fat diet, leading to dysregulated AA metabolism, excessive prostaglandin E2 (PGE2) production, aggravated inflammation, oxidative stress, and fibrosis. Conversely, adeno-associated virus (AAV)-mediated restoration of FGF21 normalized COX-derived AA metabolites, suppressed COX-2 activation, and ameliorated hepatic injury. Pharmacological inhibition of COX-2 partially recapitulated the protective effects of FGF21 but failed to reverse fibrosis, suggesting that COX-2 contributes to disease progression but is not sufficient to account for fibrosis. Mechanistically, FGF21 suppressed COX-2 through a PPARα-dependent pathway, whereas ERK1/2 phosphorylation acted upstream of the FGF21/PPARα axis. In patients with MASLD, circulating PGE2 was positively associated with liver injury after adjustment for body mass index and hepatic steatosis. Collectively, the FGF21-PPARα-COX-2 axis represents a critical regulator of AA metabolic remodeling and a potential therapeutic target for MASLD.

Neurodegenerative diseases arise from interacting oxidative, inflammatory, mitochondrial, and proteostatic disturbances. Hydroxytyrosol (HT), an olive phenol, has been proposed as a multitarget neuroprotective compound. This narrative review integrates HT chemistry, parent/metabolite pharmacokinetics, blood-brain barrier (BBB) evidence, mechanisms, disorder-specific models, and human studies. Direct HT evidence is strongest for nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) activation and experimental modulation of α-synuclein; support for AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mitochondrial protection, nuclear factor-kappa B (NF-κB)-related inflammation, and amyloid-β (Aβ) is predominantly preclinical, whereas tau, autophagic flux, and ubiquitin-proteasome effects remain preliminary. Oral HT is rapidly absorbed but extensively conjugated, and no study has quantified parent HT or its major metabolites in the human brain or cerebrospinal fluid after oral supplementation. Isolated-HT trials show systemic antioxidant or anti-inflammatory biomarker effects, while cognitive findings derive mainly from phenolic-rich olive matrices and cannot be assigned to HT alone. No disease-modifying efficacy has been established for isolated HT in Alzheimer's disease (AD), Parkinson's disease (PD), or related disorders. HT is therefore a mechanistically plausible candidate, but human brain exposure, dose-response, and efficacy require adequately powered disease-specific trials.

Fatty liver hemorrhagic syndrome (FLHS) is a prevalent metabolic disease in laying hens, causing severe economic losses. A previous study showed that conjugated linoleic acids (CLA) alleviated estrogen-induced FLHS in chickens, but the mechanism remains unclear. In the present study, we found that CLA improved serum lipid homeostasis, reduced hepatic lipid accumulation, and enhanced antioxidant activity in FLHS chickens. Transcriptome analysis identified differentially expressed genes enriched in inflammatory response, lipid homeostasis, carbohydrate metabolism, and mitogen-activated protein kinase (MAPK)/peroxisome proliferator-activated receptor (PPAR)/insulin signaling pathways. Metabolome analysis detected differentially abundant metabolites enriched in bile secretion, thyroid hormone synthesis, the insulin signaling pathway, and glycerophospholipid metabolism. Integrated analyses revealed that CLA reshaped the hepatic metabolic profile by upregulating protective metabolites (such as ubiquinol) and downregulating pro-inflammatory/lipogenic metabolites (such as 15-hydroperoxyeicosa-8Z,11Z,13E-trienoate), which synergized with key gene regulation (fatty acid synthase, jun proto-oncogene, and fatty acid desaturase 2) and core pathway activity (MAPK/nuclear factor kappa-B inhibition, PPARα activation). The multi-omics study using an estradiol-induced rooster FLHS model elucidated the molecular regulatory network of CLA against hepatic steatosis and liver injury, and provided preliminary mechanistic clues for developing CLA functional additives to prevent and treat FLHS in commercial laying hens.