IDH2
S. cerevisiae
isocitrate dehydrogenase (NAD(+)) IDH2
What the model saw
Gene: IDH2 Organism: Saccharomyces cerevisiae Known functions: isocitrate dehydrogenase (NAD(+)) IDH2. NAD binding. isocitrate dehydrogenase (NAD+) activity. magnesium ion binding. oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor. protein binding.
View unredacted entry
isocitrate dehydrogenase (NAD(+)) IDH2. NAD binding. isocitrate dehydrogenase (NAD+) activity. magnesium ion binding. oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor. protein binding.
Solver output
IDH2 encodes the mitochondrial NAD+-dependent isocitrate dehydrogenase, which catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the TCA cycle. This reaction generates NADH for the electron transport chain and is a key step in mitochondrial energy metabolism. Proper TCA cycle flux supports mitochondrial membrane potential and ATP production, opposing mitochondrial dysfunction — a hallmark of aging. Additionally, alpha-ketoglutarate produced by IDH2 is a substrate for alpha-ketoglutarate-dependent dioxygenases involved in epigenetic regulation and collagen synthesis, and elevated alpha-ketoglutarate has been linked to lifespan extension. In yeast, loss of mitochondrial TCA cycle activity accelerates aging, while robust mitochondrial respiration is associated with chronological and replicative longevity. The NAD+ consumption/regeneration balance maintained by IDH2 also feeds into sirtuin activity, further supporting pro-longevity signaling.
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 pro_longevity with 0.72 confidence, but the ground truth is anti_longevity. IDH2 in yeast is actually anti-longevity, meaning its deletion or reduction extends lifespan. The model's reasoning is plausible in general terms (TCA cycle, NAD+/NADH balance, alpha-ketoglutarate signaling) but misses the actual yeast-specific finding. In yeast, IDH2 activity can actually shorten lifespan — possibly because IDH2 competes with other metabolic pathways or because its deletion redirects carbon flux in ways that extend lifespan. The model applied generic reasoning about mitochondrial function being pro-longevity without accounting for the specific yeast biology where IDH2 is anti-longevity. The reasoning quality is low because it confidently reached the wrong conclusion using plausible-sounding but ultimately incorrect logic for this specific gene/organism combination.
Raw API responses
solver
{
"reasoning": "IDH2 encodes the mitochondrial NAD+-dependent isocitrate dehydrogenase, which catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the TCA cycle. This reaction generates NADH for the electron transport chain and is a key step in mitochondrial energy metabolism. Proper TCA cycle flux supports mitochondrial membrane potential and ATP production, opposing mitochondrial dysfunction — a hallmark of aging. Additionally, alpha-ketoglutarate produced by IDH2 is a substrate for alpha-ketoglutarate-dependent dioxygenases involved in epigenetic regulation and collagen synthesis, and elevated alpha-ketoglutarate has been linked to lifespan extension. In yeast, loss of mitochondrial TCA cycle activity accelerates aging, while robust mitochondrial respiration is associated with chronological and replicative longevity. The NAD+ consumption/regeneration balance maintained by IDH2 also feeds into sirtuin activity, further supporting pro-longevity signaling.",
"confidence": 0.72,
"key_pathways": [
"TCA cycle / mitochondrial respiration",
"NAD+/NADH redox balance and sirtuin signaling",
"alpha-ketoglutarate-dependent metabolic signaling"
],
"mechanism_class": "mitochondrial_dysfunction",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted pro_longevity with 0.72 confidence, but the ground truth is anti_longevity. IDH2 in yeast is actually anti-longevity, meaning its deletion or reduction extends lifespan. The model's reasoning is plausible in general terms (TCA cycle, NAD+/NADH balance, alpha-ketoglutarate signaling) but misses the actual yeast-specific finding. In yeast, IDH2 activity can actually shorten lifespan — possibly because IDH2 competes with other metabolic pathways or because its deletion redirects carbon flux in ways that extend lifespan. The model applied generic reasoning about mitochondrial function being pro-longevity without accounting for the specific yeast biology where IDH2 is anti-longevity. The reasoning quality is low because it confidently reached the wrong conclusion using plausible-sounding but ultimately incorrect logic for this specific gene/organism combination.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}