SDH1
S. cerevisiae
succinate dehydrogenase flavoprotein subunit SDH1
What the model saw
Gene: SDH1 Organism: Saccharomyces cerevisiae Known functions: succinate dehydrogenase flavoprotein subunit SDH1. electron transfer activity. flavin adenine dinucleotide binding. oxidoreductase activity. oxidoreductase activity, acting on the CH-CH group of donors. protein binding. succinate dehydrogenase (FAD) activity. succinate dehydrogenase (quinone) activity.
View unredacted entry
succinate dehydrogenase flavoprotein subunit SDH1. electron transfer activity. flavin adenine dinucleotide binding. oxidoreductase activity. oxidoreductase activity, acting on the CH-CH group of donors. protein binding. succinate dehydrogenase (FAD) activity. succinate dehydrogenase (quinone) activity.
Solver output
SDH1 encodes the catalytic flavoprotein subunit of succinate dehydrogenase (Complex II), which oxidizes succinate to fumarate in the TCA cycle while transferring electrons to ubiquinone in the mitochondrial electron transport chain. Proper Complex II function is essential for efficient mitochondrial respiration and ATP production; loss of SDH1 impairs both TCA cycle flux and ETC electron flow, leading to succinate accumulation, increased reactive oxygen species (ROS) production, and mitochondrial dysfunction. In yeast, functional mitochondrial respiration is strongly associated with chronological and replicative lifespan extension, and SDH1 mutants show reduced respiratory capacity. Additionally, succinate accumulation resulting from SDH1 loss can act as an oncometabolite-like signal and inhibit alpha-ketoglutarate-dependent dioxygenases, potentially causing epigenetic dysregulation. Thus, the normal function of SDH1 supports mitochondrial integrity and metabolic efficiency, promoting longevity.
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. SDH1 in yeast is anti-longevity, meaning its normal function shortens lifespan (or its deletion extends lifespan). The model's reasoning assumed that because SDH1 supports mitochondrial respiration, it must be pro-longevity. However, in yeast chronological lifespan studies, SDH1 deletion has been shown to extend lifespan, likely because reduced TCA/ETC activity can trigger mitohormesis or reduce ROS production in certain contexts. The model's mechanistic reasoning was also flawed - it correctly identified SDH1's role in Complex II and TCA cycle, but incorrectly concluded that this function promotes longevity. The model failed to consider that in yeast, reduced mitochondrial respiration (particularly through the TCA cycle) can actually extend chronological lifespan through mechanisms like reduced acetic acid production or altered metabolic signaling. The reasoning about succinate accumulation and ROS was partially relevant but led to the wrong conclusion.
Raw API responses
solver
{
"reasoning": "SDH1 encodes the catalytic flavoprotein subunit of succinate dehydrogenase (Complex II), which oxidizes succinate to fumarate in the TCA cycle while transferring electrons to ubiquinone in the mitochondrial electron transport chain. Proper Complex II function is essential for efficient mitochondrial respiration and ATP production; loss of SDH1 impairs both TCA cycle flux and ETC electron flow, leading to succinate accumulation, increased reactive oxygen species (ROS) production, and mitochondrial dysfunction. In yeast, functional mitochondrial respiration is strongly associated with chronological and replicative lifespan extension, and SDH1 mutants show reduced respiratory capacity. Additionally, succinate accumulation resulting from SDH1 loss can act as an oncometabolite-like signal and inhibit alpha-ketoglutarate-dependent dioxygenases, potentially causing epigenetic dysregulation. Thus, the normal function of SDH1 supports mitochondrial integrity and metabolic efficiency, promoting longevity.",
"confidence": 0.72,
"key_pathways": [
"TCA cycle / succinate oxidation",
"Mitochondrial electron transport chain (Complex II)",
"Reactive oxygen species homeostasis"
],
"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. SDH1 in yeast is anti-longevity, meaning its normal function shortens lifespan (or its deletion extends lifespan). The model's reasoning assumed that because SDH1 supports mitochondrial respiration, it must be pro-longevity. However, in yeast chronological lifespan studies, SDH1 deletion has been shown to extend lifespan, likely because reduced TCA/ETC activity can trigger mitohormesis or reduce ROS production in certain contexts. The model's mechanistic reasoning was also flawed - it correctly identified SDH1's role in Complex II and TCA cycle, but incorrectly concluded that this function promotes longevity. The model failed to consider that in yeast, reduced mitochondrial respiration (particularly through the TCA cycle) can actually extend chronological lifespan through mechanisms like reduced acetic acid production or altered metabolic signaling. The reasoning about succinate accumulation and ROS was partially relevant but led to the wrong conclusion.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}