Mitochondrial DNA Double-Strand Breaks in Oligodendrocytes Cause Demyelination, Axonal Injury, and CNS Inflammation

Abstract

Mitochondrial dysfunction has been implicated in the pathophysiology of neurodegenerative disorders, including multiple sclerosis (MS). To date, the investigation of mitochondrial dysfunction in MS has focused exclusively on neurons, with no studies exploring whether dysregulation of mitochondrial bioenergetics and/or genetics in oligodendrocytes might be associated with the etiopathogenesis of MS and other demyelinating syndromes. To address this question, we established a mouse model where mitochondrial DNA (mtDNA) double-strand breaks (DSBs) were specifically induced in myelinating oligodendrocytes (PLP:mtPstI mice) by expressing a mitochondrial-targeted endonuclease, mtPstI, starting at 3 weeks of age. In both female and male mice, DSBs of oligodendroglial mtDNA caused impairment of locomotor function, chronic demyelination, glial activation, and axonal degeneration, which became more severe with time of induction. In addition, after short transient induction of mtDNA DSBs, PLP:mtPstI mice showed an exacerbated response to experimental autoimmune encephalomyelitis. Together, our data demonstrate that mtDNA damage can cause primary oligodendropathy, which in turn triggers demyelination, proving PLP:mtPstI mice to be a useful tool to study the pathological consequences of mitochondrial dysfunction in oligodendrocytes. In addition, the demyelination and axonal loss displayed by PLP:mtPstI mice recapitulate some of the key features of chronic demyelinating syndromes, including progressive MS forms, which are not accurately reproduced in the models currently available. For this reason, the PLP:mtPstI mouse represents a unique and much needed platform for testing remyelinating therapies. In this study, we show that oligodendrocyte-specific mitochondrial DNA double-strand breaks in PLP:mtPstI mice cause oligodendrocyte death and demyelination associated with axonal damage and glial activation. Hence, PLP:mtPstI mice represent a unique tool to study the pathological consequences of mitochondrial dysfunction in oligodendrocytes, as well as an ideal platform to test remyelinating and neuroprotective agents.

Sphingosine-1-Phosphate Receptor Modulators and Oligodendroglial Cells: Beyond Immunomodulation

“…The exact mechanisms behind this remain unclear; however, several essential pathways involved in DNA damage and repair, the epigenetic machinery and metabolic processes might be involved. The higher occurrence of oxidative DNA damage and impaired repair compared to other CNS cell types, challenge the genomic stability of OPCs [ 51 , 123 , 124 ]. Furthermore, ROS can negatively impact DNA methylation, histone acetylation, and miRNA presence, which are all deemed necessary in OPC differentiation and especially relieving its blocking mechanisms [ 26 , 125 , 126 , 127 , 128 ].…”

On elucidation of the role of mitochondria dysfunction and oxidative stress in multiple sclerosis

“…Mitochondrial abnormalities and energy failure promote increased demyelination and inflammation in neurons and tissues affected by MS, exacerbating the disease. MtD can cause primary oligodendropathy, triggering demyelination . Also, MtD has been found to play a key role in a progressive axonal loss in MS .…”

“…MtD can cause primary oligodendropathy, triggering demyelination. 34 Also, MtD has been found to play a key role in a progressive axonal loss in MS. 17,35,36 Following axonal demyelination in MS, it has been hypothesized that mitochondria play a greater role in maintaining axonal function as an adaptive process to the increased energy need of demyelinated axons but MtD results over time leading to severe and chronic axonal damage. 35,37,38 F I G U R E 1 The role of mitochondria dysfunction and oxidative stress in MS | 307 TOBORE Aside from MtD, OS plays a role in demyelination and axonal damage in MS. [39][40][41][42] Findings from several studies have suggested that OS plays the most important role in the demyelination and neurodegeneration observed in MS. [42][43][44][45][46] OS causes selective oligodendrocyte death and can disrupt the process of oligodendrocyte differentiation, leading to demyelination.…”

Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs

“…1). 41,[59][60][61][62][63][64][65][66][67][68] Although a principal role of mitochondria is to supply the bioenergy needed for cellular processes and maintenance, 69-71 mitochondria also help regulate neurite branching and regeneration as well as synaptic strength, stability, and signaling in the CNS. 72 In addition, myelin repair is intimately dependent on healthy mitochondrial function within the CNS in oligodendrocytes and neuronal cell bodies.…”

“…72 In addition, myelin repair is intimately dependent on healthy mitochondrial function within the CNS in oligodendrocytes and neuronal cell bodies. 63,64,[73][74][75][76][77] Dysfunctional mitochondria become sources of reactive oxygen species (ROS) that contribute to OS with deleterious effects on the cell's wellbeing. 61,70,71,74,[77][78][79][80] Manifestations of OS are hallmark symptoms in neurological disease, including cognitive deficits.…”