AI Insight
Researchers identified that oxaloacetate, a key metabolic intermediate in the tricarboxylic acid cycle, can damage mitochondria when it accumulates abnormally. Through genetic screening in C. elegans and validation in mammalian cells, they discovered that excess oxaloacetate binds to the MICOS complex protein CHCH-3/MIC19, inhibiting its ability to promote proper mitochondrial membrane structure through MIC60. This accumulation occurs when enzymes that normally process oxaloacetate—either converting it downstream (PCK-1/2) or to aspartate (GOT-2.1/2.2)—are deficient, resulting in disrupted mitochondrial cristae and severe organellar damage.
Why it matters
This work provides the first clear molecular mechanism explaining how oxaloacetate accumulation causes mitochondrial damage in organic acidemias and related metabolic disorders. Understanding this pathway through the MICOS complex could enable development of targeted therapies for patients suffering from these currently devastating and poorly understood mitochondrial diseases.
Understand the Science
by Jie Zhang, Qian Shan, Xin Wang, Meijiao Li, Yang Yang, Mei Duan, Ruofeng Tang, Junxiang Zhou, Fengyang Wang, Yuehui Shi, Kai Jiang, Chonglin Yang
Mitochondria catabolize nutrients by generating sequentially-ordered organic acid intermediates that are oxidized through the tricarboxylic acid cycle. Pathogenic accumulation of metabolic organic acids manifests as devastating organic acidemias/acidurias and other severe diseases, but the underlying mechanisms are largely unknown. Using unbiased C. elegans genetic screening, we here reveal that mutations in the phosphoenolpyruvate carboxykinases PCK-1 and PCK-2 cause buildup of oxaloacetate, a key tricarboxylic acid cycle intermediate, leading to severe mitochondrial damage. Depletion of mitochondrial GOT-2.1 or GOT-2.2, which catalyze oxaloacetate conversion to aspartate, also causes oxaloacetate accumulation and defective mitochondria with disrupted cristae. We demonstrate that oxaloacetate binds the MICOS complex subunit CHCH-3/MIC19 and inhibits its function of promoting IMMT-1/MIC60-dependent membrane shaping and remodeling. In mammalian cells, aberrant OAA buildup similarly causes mitochondrial impairment through MIC19 and MIC60. These findings not only provide important mechanistic insights into mitochondrial damage in the context of defective oxaloacetate metabolism, but also suggest therapeutic strategies for oxaloacetate-related mitochondriopathies.
Source: Oxaloacetate damages mitochondria by perturbing MIC60-dependent membrane remodeling