mdh-2
C. elegans
Malate dehydrogenase, mitochondrial
What the model saw
Gene: mdh-2 Organism: Caenorhabditis elegans Known functions: Malate dehydrogenase, mitochondrial. 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, mitochondrial. 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
MDH-2 encodes the mitochondrial malate dehydrogenase, which catalyzes the reversible oxidation of L-malate to oxaloacetate using NAD+ as a cofactor — a critical step in the tricarboxylic acid (TCA) cycle. Proper TCA cycle flux is essential for efficient mitochondrial oxidative phosphorylation and ATP production. By regenerating oxaloacetate and maintaining NAD+/NADH balance within the mitochondrial matrix, MDH-2 supports mitochondrial respiratory chain function and reduces electron leak that would otherwise generate damaging reactive oxygen species (ROS). In C. elegans, mitochondrial metabolic efficiency is tightly linked to lifespan, as seen in multiple longevity pathways (e.g., daf-2/IIS, eat-2 dietary restriction) that converge on mitochondrial function. Loss of mdh-2 would impair TCA cycle integrity, reduce mitochondrial membrane potential, and increase oxidative stress — all hallmarks of mitochondrial dysfunction associated with shortened lifespan.
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 mdh-2. The mechanistic reasoning is sound and well-grounded: MDH-2 as mitochondrial malate dehydrogenase supports TCA cycle function, NAD+/NADH balance, and mitochondrial efficiency, with loss-of-function expected to impair these processes and shorten lifespan. The reasoning is biologically coherent and consistent with known C. elegans longevity biology. The confidence of 0.72 is appropriate. Minor note: the model frames the mechanism primarily around loss-of-function causing shortened lifespan (implying pro-longevity by presence), which is the correct logical framing. The mechanism_class "mitochondrial_dysfunction" is a reasonable label for what would happen upon loss of this gene.
Raw API responses
solver
{
"reasoning": "MDH-2 encodes the mitochondrial malate dehydrogenase, which catalyzes the reversible oxidation of L-malate to oxaloacetate using NAD+ as a cofactor — a critical step in the tricarboxylic acid (TCA) cycle. Proper TCA cycle flux is essential for efficient mitochondrial oxidative phosphorylation and ATP production. By regenerating oxaloacetate and maintaining NAD+/NADH balance within the mitochondrial matrix, MDH-2 supports mitochondrial respiratory chain function and reduces electron leak that would otherwise generate damaging reactive oxygen species (ROS). In C. elegans, mitochondrial metabolic efficiency is tightly linked to lifespan, as seen in multiple longevity pathways (e.g., daf-2/IIS, eat-2 dietary restriction) that converge on mitochondrial function. Loss of mdh-2 would impair TCA cycle integrity, reduce mitochondrial membrane potential, and increase oxidative stress — all hallmarks of mitochondrial dysfunction associated with shortened lifespan.",
"confidence": 0.72,
"key_pathways": [
"TCA cycle / mitochondrial oxidative metabolism",
"NAD+/NADH redox balance",
"mitochondrial reactive oxygen species regulation"
],
"mechanism_class": "mitochondrial_dysfunction",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model correctly predicted pro_longevity for mdh-2. The mechanistic reasoning is sound and well-grounded: MDH-2 as mitochondrial malate dehydrogenase supports TCA cycle function, NAD+/NADH balance, and mitochondrial efficiency, with loss-of-function expected to impair these processes and shorten lifespan. The reasoning is biologically coherent and consistent with known C. elegans longevity biology. The confidence of 0.72 is appropriate. Minor note: the model frames the mechanism primarily around loss-of-function causing shortened lifespan (implying pro-longevity by presence), which is the correct logical framing. The mechanism_class \"mitochondrial_dysfunction\" is a reasonable label for what would happen upon loss of this gene.",
"failure_mode": "correct",
"answer_correct": true,
"mechanism_correct": true,
"reasoning_quality": 4,
"ground_truth_questionable": false
}