| RRC ID |
76347
|
| Author |
Zhou J, Duan M, Wang X, Zhang F, Zhou H, Ma T, Yin Q, Zhang J, Tian F, Wang G, Yang C.
|
| Title |
A feedback loop engaging propionate catabolism intermediates controls mitochondrial morphology.
|
| Journal |
Nat Cell Biol
|
| Abstract |
D-2-Hydroxyglutarate (D-2HG) is an α-ketoglutarate-derived mitochondrial metabolite that causes D-2-hydroxyglutaric aciduria, a devastating developmental disorder. How D-2HG adversely affects mitochondria is largely unknown. Here, we report that in Caenorhabditis elegans, loss of the D-2HG dehydrogenase DHGD-1 causes D-2HG accumulation and mitochondrial damage. The excess D-2HG leads to a build-up of 3-hydroxypropionate (3-HP), a toxic metabolite in mitochondrial propionate oxidation, by inhibiting the 3-HP dehydrogenase HPHD-1. We demonstrate that 3-HP binds the MICOS subunit MIC60 (encoded by immt-1) and inhibits its membrane-binding and membrane-shaping activities. We further reveal that dietary and gut bacteria affect mitochondrial health by modulating the host production of 3-HP. These findings identify a feedback loop that links the toxic effects of D-2HG and 3-HP on mitochondria, thus providing important mechanistic insights into human diseases related to D-2HG and 3-HP.
|
| Volume |
24(4)
|
| Pages |
526-537
|
| Published |
2022-4-1
|
| DOI |
10.1038/s41556-022-00883-2
|
| PII |
10.1038/s41556-022-00883-2
|
| PMID |
35418624
|
| MeSH |
Brain Diseases, Metabolic, Inborn* / metabolism
Feedback
Glutarates / metabolism
Humans
Isocitrate Dehydrogenase / metabolism
Mitochondria / metabolism
Oxidoreductases
Propionates* / metabolism
|
| Resource |
| C.elegans |
|
