Mitochondrial spongiotic brain disease: astrocytic stress and harmful rapamycin and ketosis effect
AffiliationStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
MetadataShow full item record
AbstractMitochondrial 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.
CitationIgnatenko O, Nikkanen J, Kononov A, Zamboni N, Ince-Dunn G, Suomalainen A. Mitochondrial spongiotic brain disease: astrocytic stress and harmful rapamycin and ketosis effect. Life Sci Alliance. 2020;3(9).
JournalLife Science Alliance
- Loss of mtDNA activates astrocytes and leads to spongiotic encephalopathy.
- Authors: Ignatenko O, Chilov D, Paetau I, de Miguel E, Jackson CB, Capin G, Paetau A, Terzioglu M, Euro L, Suomalainen A
- Issue date: 2018 Jan 4
- Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA depletion.
- Authors: Sarzi E, Goffart S, Serre V, Chrétien D, Slama A, Munnich A, Spelbrink JN, Rötig A
- Issue date: 2007 Dec
- TWINKLE is an essential mitochondrial helicase required for synthesis of nascent D-loop strands and complete mtDNA replication.
- Authors: Milenkovic D, Matic S, Kühl I, Ruzzenente B, Freyer C, Jemt E, Park CB, Falkenberg M, Larsson NG
- Issue date: 2013 May 15
- Human mitochondrial DNA replication machinery and disease.
- Authors: Young MJ, Copeland WC
- Issue date: 2016 Jun
- Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion.
- Authors: Hakonen AH, Isohanni P, Paetau A, Herva R, Suomalainen A, Lönnqvist T
- Issue date: 2007 Nov