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 (TwKO(astro)) show wide-spread cell-autonomous astrocyte activation and mitochondrial integrated stress response (ISR(mt)) induction with major metabolic remodeling of the brain. Mice with neuronal-specific TwKO show no ISR(mt) Both KD and rapamycin lead to rapid deterioration and weight loss of TwKO(astro) and premature trial termination. Although rapamycin had no robust effects on TwKO(astro) brain pathology, KD exacerbated spongiosis, gliosis, and ISR(mt) 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.