Mitochondrial spongiotic brain disease: astrocytic stress and harmful rapamycin and ketosis effect

Olesia Ignatenko,Joni Nikkanen,Gulayse Ince-Dunn,Anu Suomalainen,Alexander Kononov,Nicola Zamboni

doi:10.26508/lsa.202000797

Abstract

Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is a group of severe, tissue-specific diseases of childhood with unknown pathogenesis. Brain-specific MDS manifests as devastating spongiotic encephalopathy with no curative therapy. Here, we report cell type-specific stress responses and effects of rapamycin treatment and ketogenic diet (KD) in mice with spongiotic encephalopathy mimicking human MDS, as these interventions were reported to improve some mitochondrial disease signs or symptoms. These mice with astrocyte-specific knockout of Twnk gene encoding replicative mtDNA helicase Twinkle (TwKOastro) show wide-spread cell-autonomous astrocyte activation and mitochondrial integrated stress response (ISRmt) induction with major metabolic remodeling of the brain. Mice with neuronal-specific TwKO show no ISRmt Both KD and rapamycin lead to rapid deterioration and weight loss of TwKOastro and premature trial termination. Although rapamycin had no robust effects on TwKOastro brain pathology, KD exacerbated spongiosis, gliosis, and ISRmt Our evidence emphasizes that mitochondrial disease treatments and stress responses are tissue- and disease specific. Furthermore, rapamycin and KD are deleterious in MDS-linked spongiotic encephalopathy, pointing to a crucial role of diet and metabolism for mitochondrial disease progression.

Highlights

Mitochondrial dysfunction is emerging as a common contributor to different degenerative disorders, including neurodegeneration (Gorman et al, 2016)
The topic is especially important for mitochondrial diseases that show an exceptional variability of manifestations, despite the primary origin being in one organelle
We demonstrate that astrocytes and neurons respond differently to metabolic stress caused by TwKO and Mitochondrial DNA (mtDNA) loss

Summary

Introduction

Mitochondrial dysfunction is emerging as a common contributor to different degenerative disorders, including neurodegeneration (Gorman et al, 2016). Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an excellent example of tissue-specific mitochondrial diseases, manifesting either in the brain, liver, or muscle (Suomalainen & Isohanni, 2010). TwKOastro mice had a very different disease course They developed an early-onset neurological disease and progressive spongiotic encephalopathy, with massive cellautonomous activation of astrocytes (from here on, called cellautonomous astrogliosis). Such histological findings characterize brain-specific MDS in children (Alpers, 1931; Sandbank & Lerman, 1972). The findings from TwKOneuro and TwKOastro suggest that astrocytes are the primary affected cell type in spongiotic pathology in MDS.

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