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Mito-TIPTP Increases Mitochondrial Function by Repressing the Rubicon-p22phox Interaction in Colitis-Induced Mice.

ABSTRACT: The run/cysteine-rich-domain-containing Beclin1-interacting autophagy protein (Rubicon) is essential for the regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by interacting with p22phox to trigger the production of reactive oxygen species (ROS) in immune cells. In a previous study, we demonstrated that the interaction of Rubicon with p22phox increases cellular ROS levels. The correlation between Rubicon and mitochondrial ROS (mtROS) is poorly understood. Here, we report that Rubicon interacts with p22phox in the outer mitochondrial membrane in macrophages and patients with human ulcerative colitis. Upon lipopolysaccharide (LPS) activation, the binding of Rubicon to p22phox was elevated, and increased not only cellular ROS levels but also mtROS, with an impairment of mitochondrial complex III and mitochondrial biogenesis in macrophages. Furthermore, increased Rubicon decreases mitochondrial metabolic flux in macrophages. Mito-TIPTP, which is a p22phox inhibitor containing a mitochondrial translocation signal, enhances mitochondrial function by inhibiting the association between Rubicon and p22phox in LPS-primed bone-marrow-derived macrophages (BMDMs) treated with adenosine triphosphate (ATP) or dextran sulfate sodium (DSS). Remarkably, Mito-TIPTP exhibited a therapeutic effect by decreasing mtROS in DSS-induced acute or chronic colitis mouse models. Thus, our findings suggest that Mito-TIPTP is a potential therapeutic agent for colitis by inhibiting the interaction between Rubicon and p22phox to recover mitochondrial function.

SUBMITTER: Kim JS

PROVIDER: S-EPMC8750874 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Retinal ganglion cells (RGCs) project their long axons, composing the optic nerve, to the brain, transmitting the visual information gathered by the retina, ultimately leading to formed vision in the visual cortex. The RGC cellular system, representing the anterior part of the visual pathway, is vulnerable to mitochondrial dysfunction and optic atrophy is a very frequent feature of mitochondrial and neurodegenerative diseases. The start of the molecular era of mitochondrial medicine, the year 1988, was marked by the identification of a maternally inherited form of optic atrophy, Leber's hereditary optic neuropathy, as the first disease due to mitochondrial DNA point mutations. The field of mitochondrial medicine has expanded enormously over the last two decades and many neurodegenerative diseases are now known to have a primary mitochondrial etiology or mitochondrial dysfunction plays a relevant role in their pathogenic mechanism. Recent technical advancements in neuro-ophthalmology, such as optical coherence tomography, prompted a still ongoing systematic re-investigation of retinal and optic nerve involvement in neurodegenerative disorders. In addition to inherited optic neuropathies, such as Leber's hereditary optic neuropathy and dominant optic atrophy, and in addition to the syndromic mitochondrial encephalomyopathies or mitochondrial neurodegenerative disorders such as some spinocerebellar ataxias or familial spastic paraparesis and other disorders, we draw attention to the involvement of the optic nerve in classic age-related neurodegenerative disorders such as Parkinson and Alzheimer disease. We here provide an overview of optic nerve pathology in these different clinical settings, and we review the possible mechanisms involved in the pathogenesis of optic atrophy. This may be a model of general value for the field of neurodegeneration. This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'.

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Mito-TIPTP Increases Mitochondrial Function by Repressing the Rubicon-p22phox Interaction in Colitis-Induced Mice.

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