Metabolic Rewiring at the Mitochondria–Peroxisome Interface: Implications for Immunity and Disease

Mitochondria and peroxisomes are metabolically coupled organelles whose cooperative functions extend well beyond energy production. Peroxisomes initiate the oxidation of very long-chain and branched-chain fatty acids, generating shortened acyl-carnitines that are then transferred to mitochondria for complete combustion. Fatty acid omega-oxidation occurs in the endoplasmic reticulum and produces dicarboxylic acid intermediates that are subsequently processed through peroxisomal beta-oxidation, linking all three compartments in lipid catabolism. Both organelles generate reactive oxygen species and are subject to tight redox regulation, with peroxisomal catalase and mitochondrial superoxide dismutases forming complementary antioxidant systems amenable to pharmacological intervention. Physical contact sites between the two organelles facilitate direct metabolite and lipid transfer and coordinate responses to metabolic stress. Beyond lipid catabolism, peroxisomes synthesise plasmalogens essential for immune cell membrane integrity and signalling, and both organelles carry components of innate immune cascades, including mitochondrial antiviral signalling protein (MAVS), which coordinates antiviral responses from both compartments. Disruption of this interface has been implicated in a growing range of immune-related and metabolic diseases, including conditions for which PPAR agonists are in established clinical use and mitochondria-targeted antioxidants are in active clinical development, yet the full pharmacological tractability of the mitochondria-peroxisome axis as a unified therapeutic target remains underexplored.

This Research Topic aims to advance understanding of the mitochondria-peroxisome metabolic interface as a pharmacologically relevant regulator of immune function and a driver of disease pathology, a question that sits at the heart of immunometabolism. The mitochondria-peroxisome axis already has a translational foundation through PPAR agonists, mitochondria-targeted antioxidants, and emerging peroxisome-modulating strategies, offering concrete pharmacological entry points on which to build. By consolidating research on metabolic, redox, lipid, and signaling crosstalk between these two organelles, this collection seeks to map how organelle-level dysfunction connects to immune dysregulation and systemic disease, and to identify and validate pharmacological strategies capable of targeting this interface therapeutically.

Studies connecting organelle biology directly to pharmacological outcomes are especially encouraged. This Research Topic welcomes original research and review articles, with contributions particularly encouraged in the following areas:

- Metabolic coupling between peroxisomes and mitochondria as a source of pharmacological targets, including fatty acid oxidation intermediates, omega-oxidation product processing, and acyl-carnitine transfer as candidate points of therapeutic intervention

- Redox regulation at the mitochondria-peroxisome interface as a target for antioxidant pharmacology, including ROS-generating and antioxidant enzymatic systems and redox-linked signaling pathways amenable to pharmacological modulation

- Pharmacological targeting of lipid remodeling and lipid mediators involved in mitochondria-peroxisome communication and immune regulation, including druggable lipid mediator pathways relevant to inflammatory and immune disease

- Roles of the mitochondria-peroxisome axis in immune cell function and immunometabolism, including macrophage polarisation, T cell metabolism, and innate antiviral signaling, and the pharmacological modulation of these processes

- MAVS-dependent and peroxisome-associated innate immune pathways as targets for antiviral and immunomodulatory drug development

- Plasmalogen biosynthesis and its pharmacological manipulation, including consequences for immune cell membrane integrity, inflammatory signalling, and lipid-targeted therapeutic strategies

- Pharmacological targeting of nuclear receptor signaling, particularly PPAR-dependent and PPAR-independent pathways, as a strategy for modulating organelle crosstalk and metabolic adaptation

- Peroxisome biogenesis, PEX gene dysfunction, and therapeutic strategies targeting peroxisome restoration, including in Zellweger spectrum disorders

- Pharmacological targeting of acetyl-CoA flux and NAD+/NADH ratios as regulators of epigenetic and immune gene expression at the mitochondria-peroxisome interface

- Pharmacological modulation of organelle quality control and turnover, including mitophagy and pexophagy inducers and inhibitors, and their therapeutic relevance in immune dysregulation and metabolic disease

- Metabolomics and lipidomics as tools for identifying drug targets, pharmacodynamic biomarkers, and treatment response signatures at the mitochondria-peroxisome interface

- The contribution of mitochondrial and peroxisomal dysfunction to chronic inflammatory disease, metabolic syndrome, neuroinflammation, and infection, with emphasis on translational and therapeutic perspectives and pharmacological rescue strategies

- Pharmacological modulation of the mitochondria-peroxisome axis, including PPAR agonists, mitochondria-targeted antioxidants, and peroxisome biogenesis modulators: mechanisms, selectivity, and therapeutic potential

- Drug discovery strategies targeting the mitochondria-peroxisome axis, including target identification and validation, lead optimisation, and preclinical translational models