Loss of mtDNA activates astrocytes and leads to spongiotic encephalopathy

Olesia Ignatenko,Anu Suomalainen,Dmitri Chilov,Liliya Euro,Elena De Miguel,Anders Paetau,Christopher B Jackson,Ilse Paetau,Gabrielle Capin,Mugen Terzioglu

doi:10.1038/s41467-017-01859-9

Olesia Ignatenko, Anu Suomalainen + Show 8 more

Open Access

https://doi.org/10.1038/s41467-017-01859-9

Copy DOI

Abstract

Mitochondrial dysfunction manifests as different neurological diseases, but the mechanisms underlying the clinical variability remain poorly understood. To clarify whether different brain cells have differential sensitivity to mitochondrial dysfunction, we induced mitochondrial DNA (mtDNA) depletion in either neurons or astrocytes of mice, by inactivating Twinkle (TwKO), the replicative mtDNA helicase. Here we show that astrocytes, the most abundant cerebral cell type, are chronically activated upon mtDNA loss, leading to early-onset spongiotic degeneration of brain parenchyma, microgliosis and secondary neurodegeneration. Neuronal mtDNA loss does not, however, cause symptoms until 8 months of age. Findings in astrocyte-TwKO mimic neuropathology of Alpers syndrome, infantile-onset mitochondrial spongiotic encephalopathy caused by mtDNA maintenance defects. Our evidence indicates that (1) astrocytes are dependent on mtDNA integrity; (2) mitochondrial metabolism contributes to their activation; (3) chronic astrocyte activation has devastating consequences, underlying spongiotic encephalopathy; and that (4) astrocytes are a potential target for interventions.

Highlights

Mitochondrial dysfunction manifests as different neurological diseases, but the mechanisms underlying the clinical variability remain poorly understood
The results propose that primary astrocyte dysfunction underlies mitochondrial spongiotic encephalopathies, such as Alpers syndrome, caused by mitochondrial DNA (mtDNA) maintenance defects
To clarify whether mtDNA maintenance is essential for neurons and glia, we designed cell-type-specific conditional knockout mice for the Twnk gene encoding mitochondrial DNA helicase Twinkle (TwKO) (Fig. 1a)

Summary

Introduction

Mitochondrial dysfunction manifests as different neurological diseases, but the mechanisms underlying the clinical variability remain poorly understood. Findings in astrocyte-TwKO mimic neuropathology of Alpers syndrome, infantile-onset mitochondrial spongiotic encephalopathy caused by mtDNA maintenance defects. Alpers–Huttenlocher syndrome is caused by recessive mutations in mitochondrial DNA (mtDNA) maintenance proteins: the nuclear-encoded DNA polymerase gamma or replicative helicase Twinkle[8,9]. These proteins, together with the mitochondrial transcription factor A (TFAM) form the minimal mtDNA replisome, and are essential for faithful mtDNA replication[10]: their total inactivation in mice is embryonic lethal at ~E8.511–13. The late manifestation of neurological symptoms in neuronal TFAM-knockout mice and the mitochondrial endonuclease over-expressor mice indicates that neurons can sustain relatively prolonged periods of mtDNA depletion and severe RC deficiency, questioning the role of neurons as the primary culprit in mtDNA maintenance disorders

Methods

Results

Conclusion