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Objective: To investigate accumulation of disability in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein‐antibody‐associated disease (MOGAD) in a changing treatment landscape. We aimed to identify risk factors for the development of disability milestones in relation to disease duration, number of attacks, and age. Methods: We analyzed data from individuals with NMOSD and MOGAD from the German Neuromyelitis Optica Study Group registry. Applying survival analyses, we estimated risk factors and computed time to disability milestones as defined by the Expanded Disability Status Score (EDSS). Results: We included 483 patients: 298 AQP4‐IgG+ NMOSD, 52 AQP4‐IgG−/MOG‐IgG− NMOSD patients, and 133 patients with MOGAD. Despite comparable annualized attack rates, disability milestones occurred earlier and after less attacks in NMOSD patients than MOGAD patients (median time to EDSS 3: AQP4‐IgG+ NMOSD 7.7 (95% CI 6.6–9.6) years, AQP4‐IgG−/MOG‐IgG− NMOSD 8.7) years, MOGAD 14.1 (95% CI 10.4–27.6) years; EDSS 4: 11.9 (95% CI 9.7–14.7), 11.6 (95% lower CI 7.6) and 20.4 (95% lower CI 14.1) years; EDSS 6: 20.1 (95% CI 16.5–32.1), 20.7 (95% lower CI 11.6), and 37.3 (95% lower CI 29.4) years; and EDSS 7: 34.2 (95% lower CI 31.1) for AQP4‐IgG+ NMOSD). Higher age at onset increased the risk for all disability milestones, while risk of disability decreased over time. Interpretation: AQP4‐IgG+ NMOSD, AQP4‐IgG−/MOG‐IgG− NMOSD, and MOGAD patients show distinctive relapse‐associated disability progression, with MOGAD having a less severe disease course. Investigator‐initiated research has led to increasing awareness and improved treatment strategies appearing to ameliorate disease outcomes for NMOSD and MOGAD. ANN NEUROL 2024;95:720–732 [ABSTRACT FROM AUTHOR]

Mitochondria are increasingly recognized as cellular hubs to orchestrate signaling pathways that regulate metabolism, redox homeostasis, and cell fate decisions. Recent research revealed a role of mitochondria also in innate immune signaling; however, the mechanisms of how mitochondria affect signal transduction are poorly understood. Here, we show that the NF‐κB pathway activated by TNF employs mitochondria as a platform for signal amplification and shuttling of activated NF‐κB to the nucleus. TNF treatment induces the recruitment of HOIP, the catalytic component of the linear ubiquitin chain assembly complex (LUBAC), and its substrate NEMO to the outer mitochondrial membrane, where M1‐ and K63‐linked ubiquitin chains are generated. NF‐κB is locally activated and transported to the nucleus by mitochondria, leading to an increase in mitochondria‐nucleus contact sites in a HOIP‐dependent manner. Notably, TNF‐induced stabilization of the mitochondrial kinase PINK1 furthermore contributes to signal amplification by antagonizing the M1‐ubiquitin‐specific deubiquitinase OTULIN. Overall, our study reveals a role for mitochondria in amplifying TNF‐mediated NF‐κB activation, both serving as a signaling platform, as well as a transport mode for activated NF‐κB to the nuclear. Synopsis: The E3 ubiquitin ligase HOIP is the catalytic component the linear ubiquitin chain assembly complex (LUBAC) that regulates canonical NF‐κB activation in innate immune signaling. This study reports a role of mitochondria in promoting TNF‐induced NF‐κB pathway activation by HOIP‐dependent reshaping of the mitochondrial membrane. LUBAC is recruited to the outer mitochondrial membrane upon TNF receptor activation.Formation of linear or M1‐linked ubiquitin chains enables the assembly of an NF‐κB signaling platform at mitochondria.PINK1 phosphorylates M1‐linked ubiquitin chains, which counteracts their OTULIN‐mediated hydrolysis.Mitochondrial motility facilitates shuttling of activated NF‐κB to the nucleus.TNF increases mitochondria‐ nucleus contact sites in a HOIP‐dependent manner. [ABSTRACT FROM AUTHOR]