Maladaptive role of peridroplet mitochondria during lipophagy disruption in pancreatic cancer
Bibliographic record
Abstract
Pancreatic ductal adenocarcinoma (PDAC) cells exhibit high metabolic flexibility, enabling survival under glucose limitation by using alternative fuels such as fatty acids. Lipophagy, a selective form of autophagy targeting lipid droplets (LDs), supports mitochondrial respiration during such nutrient stress. Our previous study demonstrated that the LSD1 inhibitor SP-2509 disrupts lipophagy independently of LSD1 inhibition, leading to LD accumulation and ATP depletion in glycolysis-suppressed PDAC cells. However, the effects of disrupted lipid homeostasis on mitochondrial function remained unclear. Here, the effects of lipid overload on mitochondrial morphology and activity were investigated under glucose-restricted conditions. SP-2509 treatment caused substantial LD accumulation with mitochondrial fragmentation and closer LD-mitochondrion spatial proximity, forming peridroplet mitochondria (PDM)-like structures. These structures were not associated with increased fatty acid oxidation; instead, they correlated with impaired mitochondrial respiration, shown by a reduced complex II/IV activity ratio. Forced mitochondrial fission alone did not reduce ATP production, suggesting lipid metabolic disruption, rather than morphological changes, drives mitochondrial dysfunction. Moreover, mitochondria relocated from perinuclear to peripheral regions following treatment, a shift associated with reduced cell viability and indicating a possible link between nuclear-mitochondrial proximity and survival under stress. Our findings challenge the prevailing view of PDM as inherently adaptive organelles. In PDAC, aberrant PDM formation under lipid stress may represent a maladaptive response contributing to metabolic vulnerability. This newly identified dysregulation of lipid and mitochondrial homeostasis may offer a new therapeutic target in treatment-resistant pancreatic cancer.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".