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. 2025 Aug 17.
doi: 10.1111/febs.70223. Online ahead of print.

Mutant p53 affects the mitochondrial proteome, promoting mitochondrial fragmentation and OXPHOS in pancreatic ductal adenocarcinoma cells

Maria Poles  1 , Raffaella Pacchiana  1 , Chiara Mortali  2 , Barbara Cisterna  3 , Nidula Mullappilly  1   4 , Adriana Celesia  1 , Federica Danzi  1 , Martina Gaspari  1   5 , Daniela Cecconi  6 , Massimo Donadelli  1 , Alessandra Fiore  1
Affiliations

Mutant p53 affects the mitochondrial proteome, promoting mitochondrial fragmentation and OXPHOS in pancreatic ductal adenocarcinoma cells

Maria Poles et al. FEBS J. .

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer marked by poor prognosis and frequent gain-of-function mutations in the TP53 tumor suppressor gene. Given the crucial role of mutant p53 in the context of metabolic reprogramming and aggressive tumor behavior, we explored its role on mitochondria, which may present a valuable therapeutic target. In this study, we characterized the unique mitochondrial proteome observed in PDAC cells harboring the gain-of-function TP53R273H mutation and discovered a strong mutant p53-dependent upregulation of myosin heavy chain 14 (MYH14), a nonmuscle myosin, implicated in mitochondrial dynamics. We deeply investigated the role of mutant p53 in the regulation of mitochondrial architecture and functionality in PDAC cells. Our morphological and morphometric analyses with transmission electron microscopy and three-dimensional confocal imaging revealed that mutant p53 induced marked mitochondrial fragmentation, whereas wild-type p53 stimulated mitochondrial elongation. Interestingly, the fragmented mitochondrial morphology is associated with higher mitochondrial respiration levels and more efficient mitochondrial cristae. These findings support the role of oncogenic mutant p53 isoforms in inducing mitochondrial fragmentation through a mechanism involving MYH14, resulting in an increased oxidative phosphorylation level that may support PDAC cell growth and aggressiveness.

Keywords: MYH14; mitochondrial dynamics; mutant p53; pancreatic ductal adenocarcinoma cancer metabolism.

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