2. Academic Validation
  3. Maladaptive role of peridroplet mitochondria during lipophagy disruption in pancreatic cancer

Maladaptive role of peridroplet mitochondria during lipophagy disruption in pancreatic cancer

  • Biochem Biophys Res Commun. 2025 Sep 30:782:152609. doi: 10.1016/j.bbrc.2025.152609.
Zhiheng Zhang 1,  Liye Fang 2,  Hiroki Furukawa 1,  Andy Huang 3,  Joshua Kranrod 3,  John M Seubert 4,  Kousei Ito 1,  Shigeki Aoki 5
Affiliations

Affiliations

  • 1 Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-city, Chiba, 260-8675, Japan.
  • 2 Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2E1, Canada.
  • 3 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, 2026-M Katz Group Centre for Pharmacy and Health Research, 11361-97 Ave, Edmonton, AB, T6G 2E1, Canada.
  • 4 Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2E1, Canada; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, 2026-M Katz Group Centre for Pharmacy and Health Research, 11361-97 Ave, Edmonton, AB, T6G 2E1, Canada.
  • 5 Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-city, Chiba, 260-8675, Japan. Electronic address: aokishigeki@chiba-u.jp.
PMID: 40915065 DOI: 10.1016/j.bbrc.2025.152609
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.

Keywords

Lipid droplet; Lipophagy; Mitochondrial dysfunction; Pancreatic cancer; Peridroplet mitochondria.

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