hach-1
C. elegans
3-hydroxyisobutyryl-CoA hydrolase, mitochondrial
What the model saw
Gene: hach-1 Organism: Caenorhabditis elegans Known functions: 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial. 3-hydroxyisobutyryl-CoA hydrolase activity.
View unredacted entry
3-hydroxyisobutyryl-CoA hydrolase, mitochondrial. 3-hydroxyisobutyryl-CoA hydrolase activity.
Solver output
hach-1 encodes a mitochondrial 3-hydroxyisobutyryl-CoA hydrolase, which catalyzes a key step in the valine catabolism pathway within the mitochondrial matrix. This enzyme hydrolyzes 3-hydroxyisobutyryl-CoA to 3-hydroxyisobutyrate, preventing the toxic accumulation of methacrylyl-CoA (an electrophilic intermediate that can alkylate and damage mitochondrial proteins and DNA). By maintaining proper flux through branched-chain amino acid (BCAA) catabolism, hach-1 supports mitochondrial metabolic integrity and reduces proteotoxic stress within the organelle. Loss of this enzyme in model organisms leads to mitochondrial dysfunction due to accumulation of reactive CoA thioesters, impairing oxidative phosphorylation and overall mitochondrial health. Proper mitochondrial function is a well-established determinant of lifespan in C. elegans, placing this gene in a pro-longevity role through mitochondrial quality maintenance.
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 about the biochemical function of hach-1 (3-hydroxyisobutyryl-CoA hydrolase in valine catabolism, preventing methacrylyl-CoA accumulation) is partially correct in terms of enzyme function, but the conclusion about longevity influence is wrong. The model assumed that because the enzyme prevents toxic intermediate accumulation, it must be pro-longevity. However, in C. elegans, hach-1 is anti-longevity, meaning its loss or reduction likely extends lifespan. This is consistent with the broader finding that mild mitochondrial dysfunction or reduced BCAA catabolism can paradoxically extend lifespan in C. elegans (hormesis). The model failed to consider this nuance and instead defaulted to the intuitive but incorrect assumption that maintaining mitochondrial metabolic integrity is always pro-longevity. The confidence of 0.62 is moderate but still wrong.
Raw API responses
solver
{
"reasoning": "hach-1 encodes a mitochondrial 3-hydroxyisobutyryl-CoA hydrolase, which catalyzes a key step in the valine catabolism pathway within the mitochondrial matrix. This enzyme hydrolyzes 3-hydroxyisobutyryl-CoA to 3-hydroxyisobutyrate, preventing the toxic accumulation of methacrylyl-CoA (an electrophilic intermediate that can alkylate and damage mitochondrial proteins and DNA). By maintaining proper flux through branched-chain amino acid (BCAA) catabolism, hach-1 supports mitochondrial metabolic integrity and reduces proteotoxic stress within the organelle. Loss of this enzyme in model organisms leads to mitochondrial dysfunction due to accumulation of reactive CoA thioesters, impairing oxidative phosphorylation and overall mitochondrial health. Proper mitochondrial function is a well-established determinant of lifespan in C. elegans, placing this gene in a pro-longevity role through mitochondrial quality maintenance.",
"confidence": 0.62,
"key_pathways": [
"valine/branched-chain amino acid catabolism",
"mitochondrial CoA thioester metabolism",
"mitochondrial proteostasis and redox homeostasis"
],
"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 about the biochemical function of hach-1 (3-hydroxyisobutyryl-CoA hydrolase in valine catabolism, preventing methacrylyl-CoA accumulation) is partially correct in terms of enzyme function, but the conclusion about longevity influence is wrong. The model assumed that because the enzyme prevents toxic intermediate accumulation, it must be pro-longevity. However, in C. elegans, hach-1 is anti-longevity, meaning its loss or reduction likely extends lifespan. This is consistent with the broader finding that mild mitochondrial dysfunction or reduced BCAA catabolism can paradoxically extend lifespan in C. elegans (hormesis). The model failed to consider this nuance and instead defaulted to the intuitive but incorrect assumption that maintaining mitochondrial metabolic integrity is always pro-longevity. The confidence of 0.62 is moderate but still wrong.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}