ogdh-1
C. elegans
2-oxoglutarate dehydrogenase, mitochondrial;oxoglutarate dehydrogenase (succinyl-transferring)
What the model saw
Gene: ogdh-1 Organism: Caenorhabditis elegans Known functions: 2-oxoglutarate dehydrogenase, mitochondrial;oxoglutarate dehydrogenase (succinyl-transferring). oxidoreductase activity, acting on the aldehyde or oxo group of donors, disulfide as acceptor. oxoglutarate dehydrogenase (succinyl-transferring) activity. thiamine pyrophosphate binding.
View unredacted entry
2-oxoglutarate dehydrogenase, mitochondrial;oxoglutarate dehydrogenase (succinyl-transferring). oxidoreductase activity, acting on the aldehyde or oxo group of donors, disulfide as acceptor. oxoglutarate dehydrogenase (succinyl-transferring) activity. thiamine pyrophosphate binding.
Solver output
OGDH-1 encodes the E1 subunit of the 2-oxoglutarate dehydrogenase complex (OGDHC), a mitochondrial enzyme that catalyzes the rate-limiting, thiamine pyrophosphate-dependent oxidative decarboxylation of alpha-ketoglutarate (2-oxoglutarate) to succinyl-CoA in the TCA cycle. This step is critical for mitochondrial energy metabolism and NADH production. However, the longevity influence is genuinely ambiguous: on one hand, reduced TCA cycle flux (e.g., via partial loss of OGDHC activity) can mimic dietary restriction or alpha-ketoglutarate accumulation, which has been shown to extend lifespan in C. elegans through inhibition of ATP synthase and mTORC1 signaling. On the other hand, full loss of OGDHC function would impair mitochondrial respiration and energy production, which is generally detrimental. The dual role of alpha-ketoglutarate as both a TCA intermediate and a signaling metabolite (e.g., as a cofactor for histone demethylases and prolyl hydroxylases) further complicates the prediction, as its accumulation upon OGDH-1 loss could have pro-longevity epigenetic effects. Given these conflicting mechanistic possibilities, a definitive directional prediction is not well-supported.
GenAge curators classify each gene's normal function as promoting (Pro-Longevity) or opposing (Anti-Longevity) longevity, based on synthesis across studies. Loss-of-function effects can vary from this depending on the manipulation.
Advisor judgment
The model predicted "unclear" while the ground truth is "anti_longevity." The model's mechanistic reasoning is actually quite good - it correctly identifies OGDH-1 as the E1 subunit of the 2-oxoglutarate dehydrogenase complex in the TCA cycle, and correctly identifies the competing mechanistic possibilities (alpha-ketoglutarate accumulation could be pro-longevity via mTORC1 inhibition, while full loss of OGDHC function would impair energy production). The model was genuinely uncertain and hedged appropriately given the complexity, but ultimately failed to commit to the correct answer (anti_longevity). The reasoning quality is high - the model considered real and relevant mechanisms - but the final prediction was wrong. This is a case of appropriate uncertainty that nonetheless missed the correct answer. The ground truth being anti_longevity suggests that loss of ogdh-1 shortens lifespan, consistent with the energy production impairment hypothesis rather than the alpha-ketoglutarate accumulation hypothesis.
Raw API responses
solver
{
"reasoning": "OGDH-1 encodes the E1 subunit of the 2-oxoglutarate dehydrogenase complex (OGDHC), a mitochondrial enzyme that catalyzes the rate-limiting, thiamine pyrophosphate-dependent oxidative decarboxylation of alpha-ketoglutarate (2-oxoglutarate) to succinyl-CoA in the TCA cycle. This step is critical for mitochondrial energy metabolism and NADH production. However, the longevity influence is genuinely ambiguous: on one hand, reduced TCA cycle flux (e.g., via partial loss of OGDHC activity) can mimic dietary restriction or alpha-ketoglutarate accumulation, which has been shown to extend lifespan in C. elegans through inhibition of ATP synthase and mTORC1 signaling. On the other hand, full loss of OGDHC function would impair mitochondrial respiration and energy production, which is generally detrimental. The dual role of alpha-ketoglutarate as both a TCA intermediate and a signaling metabolite (e.g., as a cofactor for histone demethylases and prolyl hydroxylases) further complicates the prediction, as its accumulation upon OGDH-1 loss could have pro-longevity epigenetic effects. Given these conflicting mechanistic possibilities, a definitive directional prediction is not well-supported.",
"confidence": 0.42,
"key_pathways": [
"TCA cycle / alpha-ketoglutarate metabolism",
"mitochondrial oxidative phosphorylation",
"mTORC1 / nutrient sensing via alpha-ketoglutarate"
],
"mechanism_class": "mitochondrial_dysfunction",
"longevity_influence": "unclear"
}advisor
{
"notes": "The model predicted \"unclear\" while the ground truth is \"anti_longevity.\" The model's mechanistic reasoning is actually quite good - it correctly identifies OGDH-1 as the E1 subunit of the 2-oxoglutarate dehydrogenase complex in the TCA cycle, and correctly identifies the competing mechanistic possibilities (alpha-ketoglutarate accumulation could be pro-longevity via mTORC1 inhibition, while full loss of OGDHC function would impair energy production). The model was genuinely uncertain and hedged appropriately given the complexity, but ultimately failed to commit to the correct answer (anti_longevity). The reasoning quality is high - the model considered real and relevant mechanisms - but the final prediction was wrong. This is a case of appropriate uncertainty that nonetheless missed the correct answer. The ground truth being anti_longevity suggests that loss of ogdh-1 shortens lifespan, consistent with the energy production impairment hypothesis rather than the alpha-ketoglutarate accumulation hypothesis.",
"failure_mode": "appropriately_uncertain",
"answer_correct": false,
"mechanism_correct": true,
"reasoning_quality": 4,
"ground_truth_questionable": false
}