VPH1

S. cerevisiae

H(+)-transporting V0 sector ATPase subunit a

What the model saw

Gene: VPH1
Organism: Saccharomyces cerevisiae
Known functions: H(+)-transporting V0 sector ATPase subunit a. ATPase binding. phosphatidylinositol-3,5-bisphosphate binding. protein binding. proton-transporting ATPase activity, rotational mechanism.

View unredacted entry

H(+)-transporting V0 sector ATPase subunit a. ATPase binding. phosphatidylinositol-3,5-bisphosphate binding. protein binding. proton-transporting ATPase activity, rotational mechanism.

Solver output

Predicted influence

Pro-longevity

Confidence

78%

Mechanism

Disabled macroautophagy

Reasoning

VPH1 encodes the a-subunit of the V0 sector of the vacuolar H+-ATPase (V-ATPase), which is essential for acidification of the vacuolar lumen in S. cerevisiae. Proper vacuolar acidification via the rotational proton-pumping mechanism is required for autophagosome-vacuole fusion and autophagic flux, as well as for vacuolar protease activation and proteostasis. Loss of V-ATPase function impairs autophagy, lysosomal/vacuolar degradation, and nutrient sensing through TORC1 (which requires vacuolar membrane recruitment and acidification for activation). VPH1 also binds phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2), a lipid critical for vacuolar membrane dynamics and autophagy regulation. Functional V-ATPase activity supports healthy aging by maintaining proteostasis, autophagic clearance of damaged macromolecules, and proper TORC1 signaling, all of which are established pro-longevity mechanisms in yeast.

Key pathways

V-ATPase-dependent vacuolar acidificationmacroautophagy/autophagic fluxTORC1 nutrient sensing

Longevity influence

Anti-longevity

Lifespan effect

Increase and Decrease

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

Answer

✗Incorrect

Mechanism

✗Incorrect

Reasoning quality

2/5

Failure mode

Confident wrong

Notes

The model predicted VPH1 as pro_longevity with 0.78 confidence, but the ground truth is anti_longevity. The model's reasoning is logically coherent but leads to the wrong conclusion. VPH1 is actually anti-longevity in yeast, meaning its deletion extends lifespan. The model correctly identifies VPH1's role in V-ATPase function and vacuolar acidification, but incorrectly concludes that this makes it pro-longevity. In reality, VPH1/V-ATPase activity promotes TORC1 signaling, which is a well-known anti-longevity pathway - reduced TORC1 activity extends lifespan. The model mentions TORC1 but frames it as pro-longevity rather than recognizing that VPH1 supports TORC1 activity (which shortens lifespan). The mechanism reasoning is inverted - the model correctly identifies the pathways but draws the wrong conclusion about their net effect on longevity. The model was fairly confident (0.78) in the wrong direction.

Raw API responses

solver

{
  "reasoning": "VPH1 encodes the a-subunit of the V0 sector of the vacuolar H+-ATPase (V-ATPase), which is essential for acidification of the vacuolar lumen in S. cerevisiae. Proper vacuolar acidification via the rotational proton-pumping mechanism is required for autophagosome-vacuole fusion and autophagic flux, as well as for vacuolar protease activation and proteostasis. Loss of V-ATPase function impairs autophagy, lysosomal/vacuolar degradation, and nutrient sensing through TORC1 (which requires vacuolar membrane recruitment and acidification for activation). VPH1 also binds phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2), a lipid critical for vacuolar membrane dynamics and autophagy regulation. Functional V-ATPase activity supports healthy aging by maintaining proteostasis, autophagic clearance of damaged macromolecules, and proper TORC1 signaling, all of which are established pro-longevity mechanisms in yeast.",
  "confidence": 0.78,
  "key_pathways": [
    "V-ATPase-dependent vacuolar acidification",
    "macroautophagy/autophagic flux",
    "TORC1 nutrient sensing"
  ],
  "mechanism_class": "disabled_macroautophagy",
  "longevity_influence": "pro_longevity"
}

advisor

{
  "notes": "The model predicted VPH1 as pro_longevity with 0.78 confidence, but the ground truth is anti_longevity. The model's reasoning is logically coherent but leads to the wrong conclusion. VPH1 is actually anti-longevity in yeast, meaning its deletion extends lifespan. The model correctly identifies VPH1's role in V-ATPase function and vacuolar acidification, but incorrectly concludes that this makes it pro-longevity. In reality, VPH1/V-ATPase activity promotes TORC1 signaling, which is a well-known anti-longevity pathway - reduced TORC1 activity extends lifespan. The model mentions TORC1 but frames it as pro-longevity rather than recognizing that VPH1 supports TORC1 activity (which shortens lifespan). The mechanism reasoning is inverted - the model correctly identifies the pathways but draws the wrong conclusion about their net effect on longevity. The model was fairly confident (0.78) in the wrong direction.",
  "failure_mode": "confident_wrong",
  "answer_correct": false,
  "mechanism_correct": false,
  "reasoning_quality": 2,
  "ground_truth_questionable": false
}