MDH2
S. cerevisiae
malate dehydrogenase MDH2
What the model saw
Gene: MDH2 Organism: Saccharomyces cerevisiae Known functions: malate dehydrogenase MDH2. L-malate dehydrogenase (NAD+) activity. catalytic activity. malate dehydrogenase activity. oxidoreductase activity. oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor.
View unredacted entry
malate dehydrogenase MDH2. L-malate dehydrogenase (NAD+) activity. catalytic activity. malate dehydrogenase activity. oxidoreductase activity. oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor.
Solver output
MDH2 encodes a cytosolic/peroxisomal malate dehydrogenase in S. cerevisiae that catalyzes the NAD+-dependent interconversion of malate to oxaloacetate, a key step in the TCA cycle anaplerosis and the malate-aspartate shuttle. By regenerating NAD+ and maintaining oxaloacetate flux into the TCA cycle, MDH2 supports mitochondrial respiratory capacity and efficient oxidative phosphorylation. Robust mitochondrial function and NAD+/NADH redox balance are strongly associated with longevity, as they underpin energy metabolism and reduce oxidative stress. Additionally, NAD+ availability is a central node linking sirtuin activity (Sir2 in yeast) to lifespan extension, and MDH2's role in NAD+ regeneration may indirectly support this axis. Loss of TCA cycle enzyme function in yeast is generally associated with shortened replicative or chronological lifespan, supporting a pro-longevity role for MDH2.
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 correctly predicted pro_longevity for MDH2 in S. cerevisiae. However, the mechanistic reasoning contains a notable error: MDH2 in S. cerevisiae is actually a cytosolic/peroxisomal enzyme involved in gluconeogenesis (not primarily a mitochondrial TCA cycle enzyme - that role belongs to MDH1). The model incorrectly frames MDH2 as supporting mitochondrial respiratory capacity and TCA cycle anaplerosis, and classifies the mechanism as "mitochondrial_dysfunction." MDH2 is actually important for gluconeogenesis from ethanol/acetate, and its pro-longevity role is more likely related to metabolic flexibility and carbon source utilization rather than direct mitochondrial TCA cycle function. The NAD+/NADH redox balance argument has some merit but is applied in the wrong cellular compartment context. The confidence of 0.65 is reasonable given the uncertainty.
Raw API responses
solver
{
"reasoning": "MDH2 encodes a cytosolic/peroxisomal malate dehydrogenase in S. cerevisiae that catalyzes the NAD+-dependent interconversion of malate to oxaloacetate, a key step in the TCA cycle anaplerosis and the malate-aspartate shuttle. By regenerating NAD+ and maintaining oxaloacetate flux into the TCA cycle, MDH2 supports mitochondrial respiratory capacity and efficient oxidative phosphorylation. Robust mitochondrial function and NAD+/NADH redox balance are strongly associated with longevity, as they underpin energy metabolism and reduce oxidative stress. Additionally, NAD+ availability is a central node linking sirtuin activity (Sir2 in yeast) to lifespan extension, and MDH2's role in NAD+ regeneration may indirectly support this axis. Loss of TCA cycle enzyme function in yeast is generally associated with shortened replicative or chronological lifespan, supporting a pro-longevity role for MDH2.",
"confidence": 0.65,
"key_pathways": [
"TCA cycle / malate-oxaloacetate interconversion",
"NAD+/NADH redox balance",
"mitochondrial respiratory metabolism"
],
"mechanism_class": "mitochondrial_dysfunction",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model correctly predicted pro_longevity for MDH2 in S. cerevisiae. However, the mechanistic reasoning contains a notable error: MDH2 in S. cerevisiae is actually a cytosolic/peroxisomal enzyme involved in gluconeogenesis (not primarily a mitochondrial TCA cycle enzyme - that role belongs to MDH1). The model incorrectly frames MDH2 as supporting mitochondrial respiratory capacity and TCA cycle anaplerosis, and classifies the mechanism as \"mitochondrial_dysfunction.\" MDH2 is actually important for gluconeogenesis from ethanol/acetate, and its pro-longevity role is more likely related to metabolic flexibility and carbon source utilization rather than direct mitochondrial TCA cycle function. The NAD+/NADH redox balance argument has some merit but is applied in the wrong cellular compartment context. The confidence of 0.65 is reasonable given the uncertainty.",
"failure_mode": "right_answer_wrong_reasoning",
"answer_correct": true,
"mechanism_correct": false,
"reasoning_quality": 3,
"ground_truth_questionable": false
}