SDH2
S. cerevisiae
succinate dehydrogenase iron-sulfur protein subunit SDH2
What the model saw
Gene: SDH2 Organism: Saccharomyces cerevisiae Known functions: succinate dehydrogenase iron-sulfur protein subunit SDH2. 2 iron, 2 sulfur cluster binding. electron transfer activity. iron-sulfur cluster binding. oxidoreductase activity. protein binding. succinate dehydrogenase (quinone) activity.
View unredacted entry
succinate dehydrogenase iron-sulfur protein subunit SDH2. 2 iron, 2 sulfur cluster binding. electron transfer activity. iron-sulfur cluster binding. oxidoreductase activity. protein binding. succinate dehydrogenase (quinone) activity.
Solver output
SDH2 encodes the iron-sulfur (Rieske) subunit of succinate dehydrogenase (Complex II), which couples the oxidation of succinate to fumarate in the TCA cycle with electron transfer to ubiquinone in the mitochondrial respiratory chain. Proper Complex II function is essential for maintaining mitochondrial membrane potential and efficient oxidative phosphorylation. Loss of SDH2 impairs electron flow through the respiratory chain, increases reactive oxygen species (ROS) production from electron leak, and disrupts TCA cycle flux — all hallmarks of mitochondrial dysfunction associated with accelerated aging. In yeast, functional mitochondria and intact respiratory capacity are strongly linked to chronological and replicative lifespan extension, and SDH2 mutants show reduced respiratory growth and elevated oxidative stress. Therefore, the normal function of SDH2 supports mitochondrial integrity and opposes aging-associated mitochondrial decline.
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 SDH2 as pro_longevity with 0.72 confidence, but the ground truth is anti_longevity. The model's reasoning assumes that because SDH2 supports mitochondrial function, it must be pro-longevity. However, in yeast, SDH2 (and Complex II activity more broadly) is actually anti-longevity — meaning its loss or reduction extends lifespan. This is consistent with findings that reduced mitochondrial respiration and TCA cycle activity can extend chronological lifespan in yeast, possibly through mechanisms like reduced ROS production from a less active respiratory chain, or metabolic reprogramming. The model's mechanistic reasoning is also incorrect: it assumes that functional mitochondria always promote longevity in yeast, but the relationship is more nuanced. Reduced Complex II activity can actually extend lifespan in yeast, which is why SDH2 is classified as anti_longevity (its normal function shortens lifespan). The model made a plausible but ultimately wrong assumption about the direction of effect.
Raw API responses
solver
{
"reasoning": "SDH2 encodes the iron-sulfur (Rieske) subunit of succinate dehydrogenase (Complex II), which couples the oxidation of succinate to fumarate in the TCA cycle with electron transfer to ubiquinone in the mitochondrial respiratory chain. Proper Complex II function is essential for maintaining mitochondrial membrane potential and efficient oxidative phosphorylation. Loss of SDH2 impairs electron flow through the respiratory chain, increases reactive oxygen species (ROS) production from electron leak, and disrupts TCA cycle flux — all hallmarks of mitochondrial dysfunction associated with accelerated aging. In yeast, functional mitochondria and intact respiratory capacity are strongly linked to chronological and replicative lifespan extension, and SDH2 mutants show reduced respiratory growth and elevated oxidative stress. Therefore, the normal function of SDH2 supports mitochondrial integrity and opposes aging-associated mitochondrial decline.",
"confidence": 0.72,
"key_pathways": [
"TCA cycle / succinate-fumarate oxidation",
"Mitochondrial electron transport chain (Complex II)",
"Reactive oxygen species homeostasis"
],
"mechanism_class": "mitochondrial_dysfunction",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted SDH2 as pro_longevity with 0.72 confidence, but the ground truth is anti_longevity. The model's reasoning assumes that because SDH2 supports mitochondrial function, it must be pro-longevity. However, in yeast, SDH2 (and Complex II activity more broadly) is actually anti-longevity — meaning its loss or reduction extends lifespan. This is consistent with findings that reduced mitochondrial respiration and TCA cycle activity can extend chronological lifespan in yeast, possibly through mechanisms like reduced ROS production from a less active respiratory chain, or metabolic reprogramming. The model's mechanistic reasoning is also incorrect: it assumes that functional mitochondria always promote longevity in yeast, but the relationship is more nuanced. Reduced Complex II activity can actually extend lifespan in yeast, which is why SDH2 is classified as anti_longevity (its normal function shortens lifespan). The model made a plausible but ultimately wrong assumption about the direction of effect.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}