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Mitochondrial spongiotic brain disease: astrocytic stress and harmful rapamycin and ketosis effect
Olesia Ignatenko1, Joni Nikkanen2, Alexander Kononov3
1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Insights
Mitochondrial DNA depletion syndrome (MDS) treatments like ketogenic diets and rapamycin worsened disease in mice. These findings highlight the critical, tissue-specific nature of mitochondrial diseases and their treatments.
Area of Science:
- Neuroscience
- Genetics
- Metabolic Disorders
Background:
- Mitochondrial DNA depletion syndrome (MDS) comprises severe childhood diseases with unknown causes.
- Brain-specific MDS leads to spongiotic encephalopathy, lacking effective treatments.
Purpose of the Study:
- To investigate cell type-specific stress responses in a mouse model of MDS.
- To evaluate the effects of rapamycin and ketogenic diet (KD) on brain pathology and disease progression in MDS models.
Main Methods:
- Generated astrocyte-specific knockout mice (TwKOastro) for the replicative mtDNA helicase gene Twinkle.
- Administered rapamycin and KD to TwKOastro mice to assess treatment effects.
- Analyzed cell-autonomous astrocyte activation, mitochondrial integrated stress response (ISRmt), and brain pathology.
Main Results:
- Astrocyte-specific TwKO mice exhibited widespread astrocyte activation and ISRmt with brain metabolic remodeling.
- Neuronal-specific TwKO mice did not show ISRmt.
- Both rapamycin and KD caused rapid deterioration and weight loss in TwKOastro mice, with KD exacerbating spongiosis, gliosis, and ISRmt.
Conclusions:
- Mitochondrial disease pathogenesis and treatment responses are highly tissue- and disease-specific.
- Rapamycin and KD are detrimental in this MDS-linked spongiotic encephalopathy model.
- Diet and metabolism play a critical role in the progression of mitochondrial diseases.
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.
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