Loss of mtDNA maintenance activates astrocytes and leads to spongiotic encephalopathy O.Ignatenko1, D.Chilov1, I.Paetau1, E.de Miguel2, C.B.Jackson1, G.Capin1, A.Paetau3, M.Terzioglu1, L.Euro1, A.Suomalainen1, 4, 5* 1Research Programs Unit, University of Helsinki, 2Department of Pharmacology, University of Helsinki, 3Department of Pathology, Huslab and Helsinki University Hospital and Medicum, University of Helsinki, 4Neuroscience Center, University of Helsinki, 5Department of Neurosciences, Helsinki University Hospital
Mitochondrial diseases are a highly variable group of severe human diseases, often manifesting with brain pathology and neurological phenotype. While the effects OXPHOS (oxidative phosphorylation) deficiency neurones is relatively well characterised, little is known about astrocytes besides their ability to survive OXPHOS deficiency via glycolysis upregulation. To understand cell-type specific consequences of mitochondrial dysfunction in the brain, we generated mouse lines with conditional knockout of nuclear-encoded mitochondrial DNA helicase Twinkle either in postnatal astrocytes (TwKOastro) or neurons (TwKOneuro), leading to progressive loss of mitochondrial DNA (mtDNA) and OXPHOS defect in the targeted cell type. We report that TwKOastro leads to a progressive gait disturbance, kyphosis, paraparesis, and weight loss; whereas TwKOneuro showed little phenotype before rapid deterioration at terminal stage. Both led to premature death at ~8 months of age. Loss of mtDNA in astrocytes caused little cell death, but led to remarkable astrocyte activation, progressive spongiotic encephalopathy and microgliosis, similar to the findings in infantile mitochondrial encephalopathies. Ultrastructural examination revealed presence of giant vacuolated mitochondria in astrocytes, indicating intracellular nature of vacuole formation. At later stages, loss of Calbindin-positive neurons and myelin disorganisation occurred. TwKOneuro resulted in late-onset extensive neuronal death with mild gliosis, but no spongiosis. We report that mtDNA depletion activates astrocytes, and the altered chronic metabolic state causes progressive degenerative disease of the central nervous system, similar to early-onset human spongiotic encephalopathies. Neurons, however, are relatively resistant to similar insult. Notably, phenotype of TwKOastro is strikingly different and severe, highlighting the unique role of mitochondria in modulating astrocyte function in adult brain.
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