A feedback loop engaging propionate catabolism intermediates controls mitochondrial morphology.

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.

• Authors: Junxiang Zhou, Mei Duan, Xin Wang, Fengxia Zhang, Hejiang Zhou, Tengfei Ma, Qiuyuan Yin, Jie Zhang, Fei Tian, Guodong Wang, Chonglin Yang
• Journal: Nature cell biology (Nat Cell Biol) Vol. 24 Issue 4 Pg. 526-537 (04 2022) ISSN: 1476-4679 [Electronic] England
• PMID: 35418624 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Glutarates
• Propionates
• Oxidoreductases
• Isocitrate Dehydrogenase

Topics

• Brain Diseases, Metabolic, Inborn (metabolism)
• Feedback
• Glutarates (metabolism)
• Humans
• Isocitrate Dehydrogenase (metabolism)
• Mitochondria (metabolism)
• Oxidoreductases
• Propionates (metabolism)