aco-2
C. elegans
putative aconitate hydratase, mitochondrial
What the model saw
Gene: aco-2 Organism: Caenorhabditis elegans Known functions: putative aconitate hydratase, mitochondrial. 4 iron, 4 sulfur cluster binding. aconitate hydratase activity.
View unredacted entry
putative aconitate hydratase, mitochondrial. 4 iron, 4 sulfur cluster binding. aconitate hydratase activity.
Solver output
ACO-2 is the mitochondrial aconitase, a core TCA cycle enzyme that catalyzes the isomerization of citrate to isocitrate via cis-aconitate, directly sustaining oxidative phosphorylation and mitochondrial energy production. Its [4Fe-4S] cluster is exquisitely sensitive to oxidative damage by superoxide and reactive oxygen species, making it a sentinel of mitochondrial redox status. Loss of aconitase activity impairs TCA cycle flux, reduces NADH/FADH2 generation, and compromises electron transport chain efficiency, leading to mitochondrial dysfunction—a canonical hallmark of aging. In C. elegans, maintaining robust mitochondrial aconitase activity supports ATP production and metabolic homeostasis, which are associated with normal lifespan; conversely, its inactivation accelerates aging phenotypes. Therefore, the normal function of aco-2 is pro-longevity by sustaining mitochondrial metabolic integrity.
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 but the ground truth is anti_longevity. The model's reasoning follows a logical but incorrect assumption: that maintaining TCA cycle function (via aconitase activity) would be beneficial for lifespan. In reality, aco-2 in C. elegans is anti-longevity, meaning its loss or reduction extends lifespan. This is consistent with the broader finding in C. elegans that reducing mitochondrial respiration and TCA cycle activity (e.g., through partial inhibition of the electron transport chain or metabolic enzymes) can paradoxically extend lifespan, likely through mitohormesis or reduced ROS production from a less active ETC. The model's mechanistic reasoning is plausible in isolation but fails to account for the well-established C. elegans biology where reduced mitochondrial function often extends lifespan. The model was fairly confident (0.72) in the wrong direction.
Raw API responses
solver
{
"reasoning": "ACO-2 is the mitochondrial aconitase, a core TCA cycle enzyme that catalyzes the isomerization of citrate to isocitrate via cis-aconitate, directly sustaining oxidative phosphorylation and mitochondrial energy production. Its [4Fe-4S] cluster is exquisitely sensitive to oxidative damage by superoxide and reactive oxygen species, making it a sentinel of mitochondrial redox status. Loss of aconitase activity impairs TCA cycle flux, reduces NADH/FADH2 generation, and compromises electron transport chain efficiency, leading to mitochondrial dysfunction—a canonical hallmark of aging. In C. elegans, maintaining robust mitochondrial aconitase activity supports ATP production and metabolic homeostasis, which are associated with normal lifespan; conversely, its inactivation accelerates aging phenotypes. Therefore, the normal function of aco-2 is pro-longevity by sustaining mitochondrial metabolic integrity.",
"confidence": 0.72,
"key_pathways": [
"TCA cycle / citric acid cycle",
"mitochondrial oxidative phosphorylation",
"iron-sulfur cluster redox sensing"
],
"mechanism_class": "mitochondrial_dysfunction",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted pro_longevity but the ground truth is anti_longevity. The model's reasoning follows a logical but incorrect assumption: that maintaining TCA cycle function (via aconitase activity) would be beneficial for lifespan. In reality, aco-2 in C. elegans is anti-longevity, meaning its loss or reduction extends lifespan. This is consistent with the broader finding in C. elegans that reducing mitochondrial respiration and TCA cycle activity (e.g., through partial inhibition of the electron transport chain or metabolic enzymes) can paradoxically extend lifespan, likely through mitohormesis or reduced ROS production from a less active ETC. The model's mechanistic reasoning is plausible in isolation but fails to account for the well-established C. elegans biology where reduced mitochondrial function often extends lifespan. The model was fairly confident (0.72) in the wrong direction.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}