Introduction: Derangement of axonal mitochondrial bioenergetics occurs during progressive multiple sclerosis (PMS). However, whether this is a delayed epiphenomenon or an early causative event of disease progression waits to be understood. Answering this question might further our knowledge of mechanisms underlying neurobiology of PMS and related therapy.Methods: MOG35-55-immunized NOD and PLP139-151-immunized SJL female mice were adopted as models of progressive or relapsing-remitting experimental autoimmune encephalomyelitis (EAE), respectively. Multiple parameters of mitochondrial homeostasis were analyzed in the mouse spinal cord during the early asymptomatic stage, also evaluating the effects of scavenging mitochondrial reactive oxygen species with Mito-TEMPO.Results: Almost identical lumbar spinal cord immune infiltrates consisting of Th1 cells and neutrophils without B and Th17 lymphocytes occurred early upon immunization in both mouse strains. Still, only NOD mice showed axon-restricted dysregulation of mitochondrial homeostasis, with reduced mtDNA contents and increased cristae area. Increased expression of mitochondrial respiratory complex subunits Nd2, Cox1, Atp5d, Sdha also exclu-sively occurred in lumbar spinal cord of NOD and not SJL mice. Accordingly, in this region genes regulating mitochondrial morphology (Opa1, Mfn1, Mfn2 and Atp5j2) and mitochondriogenesis (Pgc1 alpha, Foxo, Hif-1 alpha and Nrf2) were induced early upon immunization. A reduced extent of mitochondrial derangement occurred in the thoracic spinal cord. Notably, the mitochondrial radical scavenger Mito-TEMPO reduced H2O2 content and prevented both mtDNA depletion and cristae remodeling, having no effects on dysregulation of mitochondrial transcriptome. Discussion: We provide here the first evidence that axonal-restricted derangement of mitochondrial homeostasis already occurs during the asymptomatic state exclusively in a mouse model of PMS. Data further our under-standing of mechanisms related to EAE progression, and point to very early axonal mitochondrial dysfunction as central to the neuropathogenesis of MS evolution.

Early derangement of axonal mitochondria occurs in a mouse model of progressive but not relapsing-remitting multiple sclerosis / Buonvicino, Daniela; Ranieri, Giuseppe; Guasti, Daniele; Pistolesi, Alessandra; La Rocca, Antonino Iurato; Rapizzi, Elena; Chiarugi, Alberto. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - STAMPA. - 178:(2023), pp. 106015-106019. [10.1016/j.nbd.2023.106015]

Early derangement of axonal mitochondria occurs in a mouse model of progressive but not relapsing-remitting multiple sclerosis

Buonvicino, Daniela;Ranieri, Giuseppe;Guasti, Daniele;Pistolesi, Alessandra;La Rocca, Antonino Iurato;Rapizzi, Elena;Chiarugi, Alberto
2023

Abstract

Introduction: Derangement of axonal mitochondrial bioenergetics occurs during progressive multiple sclerosis (PMS). However, whether this is a delayed epiphenomenon or an early causative event of disease progression waits to be understood. Answering this question might further our knowledge of mechanisms underlying neurobiology of PMS and related therapy.Methods: MOG35-55-immunized NOD and PLP139-151-immunized SJL female mice were adopted as models of progressive or relapsing-remitting experimental autoimmune encephalomyelitis (EAE), respectively. Multiple parameters of mitochondrial homeostasis were analyzed in the mouse spinal cord during the early asymptomatic stage, also evaluating the effects of scavenging mitochondrial reactive oxygen species with Mito-TEMPO.Results: Almost identical lumbar spinal cord immune infiltrates consisting of Th1 cells and neutrophils without B and Th17 lymphocytes occurred early upon immunization in both mouse strains. Still, only NOD mice showed axon-restricted dysregulation of mitochondrial homeostasis, with reduced mtDNA contents and increased cristae area. Increased expression of mitochondrial respiratory complex subunits Nd2, Cox1, Atp5d, Sdha also exclu-sively occurred in lumbar spinal cord of NOD and not SJL mice. Accordingly, in this region genes regulating mitochondrial morphology (Opa1, Mfn1, Mfn2 and Atp5j2) and mitochondriogenesis (Pgc1 alpha, Foxo, Hif-1 alpha and Nrf2) were induced early upon immunization. A reduced extent of mitochondrial derangement occurred in the thoracic spinal cord. Notably, the mitochondrial radical scavenger Mito-TEMPO reduced H2O2 content and prevented both mtDNA depletion and cristae remodeling, having no effects on dysregulation of mitochondrial transcriptome. Discussion: We provide here the first evidence that axonal-restricted derangement of mitochondrial homeostasis already occurs during the asymptomatic state exclusively in a mouse model of PMS. Data further our under-standing of mechanisms related to EAE progression, and point to very early axonal mitochondrial dysfunction as central to the neuropathogenesis of MS evolution.
2023
178
106015
106019
Buonvicino, Daniela; Ranieri, Giuseppe; Guasti, Daniele; Pistolesi, Alessandra; La Rocca, Antonino Iurato; Rapizzi, Elena; Chiarugi, Alberto
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1304480
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