ACO2
S. cerevisiae
aconitate hydratase ACO2
What the model saw
Gene: ACO2 Organism: Saccharomyces cerevisiae Known functions: aconitate hydratase ACO2. 4 iron, 4 sulfur cluster binding. aconitate hydratase activity. protein binding.
View unredacted entry
aconitate hydratase ACO2. 4 iron, 4 sulfur cluster binding. aconitate hydratase activity. protein binding.
Solver output
ACO2 encodes mitochondrial aconitate hydratase (aconitase), which catalyzes the isomerization of citrate to isocitrate in the TCA cycle, a critical step for mitochondrial energy metabolism. Its [4Fe-4S] cluster is essential for catalytic activity and is highly sensitive to oxidative damage, particularly from superoxide and reactive oxygen species. Proper ACO2 function sustains TCA cycle flux, NADH production, and mitochondrial membrane potential, all of which are required for healthy mitochondrial function and ATP generation. Loss of aconitase activity in yeast leads to TCA cycle impairment, mitochondrial dysfunction, and accumulation of oxidative damage — phenotypes associated with shortened replicative and chronological lifespan. Maintenance of ACO2 activity therefore supports mitochondrial integrity and opposes aging-associated mitochondrial decline, placing it firmly in the pro-longevity category.
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. The model's reasoning is based on the general logic that TCA cycle enzymes support mitochondrial function and therefore longevity, but this is incorrect for ACO2 in yeast. ACO2 is actually anti-longevity, meaning its deletion or loss extends lifespan. The model failed to account for the specific role of ACO2 in yeast aging — in yeast, ACO2 (the mitochondrial aconitase) has been shown to be involved in processes that actually limit lifespan, possibly through its role in generating reactive oxygen species or through other mechanisms. The model's mechanistic reasoning was plausible-sounding but ultimately wrong in its conclusion about the direction of effect. The model assumed that because ACO2 supports TCA cycle function, it must be pro-longevity, but this is an oversimplification that missed the actual experimental finding.
Raw API responses
solver
{
"reasoning": "ACO2 encodes mitochondrial aconitate hydratase (aconitase), which catalyzes the isomerization of citrate to isocitrate in the TCA cycle, a critical step for mitochondrial energy metabolism. Its [4Fe-4S] cluster is essential for catalytic activity and is highly sensitive to oxidative damage, particularly from superoxide and reactive oxygen species. Proper ACO2 function sustains TCA cycle flux, NADH production, and mitochondrial membrane potential, all of which are required for healthy mitochondrial function and ATP generation. Loss of aconitase activity in yeast leads to TCA cycle impairment, mitochondrial dysfunction, and accumulation of oxidative damage — phenotypes associated with shortened replicative and chronological lifespan. Maintenance of ACO2 activity therefore supports mitochondrial integrity and opposes aging-associated mitochondrial decline, placing it firmly in the pro-longevity category.",
"confidence": 0.72,
"key_pathways": [
"TCA cycle / citric acid cycle",
"mitochondrial iron-sulfur cluster metabolism",
"mitochondrial energy metabolism"
],
"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. The model's reasoning is based on the general logic that TCA cycle enzymes support mitochondrial function and therefore longevity, but this is incorrect for ACO2 in yeast. ACO2 is actually anti-longevity, meaning its deletion or loss extends lifespan. The model failed to account for the specific role of ACO2 in yeast aging — in yeast, ACO2 (the mitochondrial aconitase) has been shown to be involved in processes that actually limit lifespan, possibly through its role in generating reactive oxygen species or through other mechanisms. The model's mechanistic reasoning was plausible-sounding but ultimately wrong in its conclusion about the direction of effect. The model assumed that because ACO2 supports TCA cycle function, it must be pro-longevity, but this is an oversimplification that missed the actual experimental finding.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}