Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0026986 (
myelodysplastic syndrome
)
14,926
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
Life Sci
Alliance
2020 09
PMID:Mitochondrial spongiotic brain disease: astrocytic stress and harmful rapamycin and ketosis effect. 3273 78
