Probing the Link between Pancratistatin and Mitochondrial Apoptosis through Changes in the Membrane Dynamics on the Nanoscale

Published

June 6, 2022

Author(s)

Stuart R. Castillo, Brett W. Rickeard, Mitchell DiPasquale, Michael H. Nguyen, Aislyn Lewis-Laurent, Milka Doktorova, Batuhan Kav, Markus S. Miettinen, Michihiro Nagao, Elizabeth Kelley, Drew Marquardt

Abstract

Pancratistatin (PST) is a natural antiviral alkaloid that has demonstrated specificity towards cancerous cells and explicitly targets the mitochondria. PST initiates apoptosis while leaving healthy, noncancerous cells unscathed. However, the manner by which PST induces apoptosis remains elusive and impedes the advancement of PST as a natural anticancer therapeutic agent. Herein, we use neutron spin-echo (NSE), molecular dynamic (MD) simulations, and supporting small angle scattering techniques to study PST's effect on membrane dynamics using biologically representative model membranes. Our data suggests that PST stiffens the inner mitochondrial membrane (IMM) by preferentially associating with cardiolipin, which would lead to the relocation and release of cytochrome c. Secondly, PST has an ordering effect on the lipids and disrupts their distribution within the IMM, which would interfere with the maintenance and functionality of the active forms of proteins in the electron transport chain. These previously unreported findings implicate PST's effect on mitochondrial apoptosis.

Citation

Molecular Pharmaceutics

Volume

19

Issue

6

Pub Type

Journals

Download Paper

https://doi.org/10.1021/acs.molpharmaceut.1c00926

Local Download

Keywords

Pancratistatin, lipid membrane rigidity, neutron spin echo spectroscopy

Citation

Castillo, S. , Rickeard, B. , DiPasquale, M. , Nguyen, M. , Lewis-Laurent, A. , Doktorova, M. , Kav, B. , Miettinen, M. , Nagao, M. , Kelley, E. and Marquardt, D. (2022), Probing the Link between Pancratistatin and Mitochondrial Apoptosis through Changes in the Membrane Dynamics on the Nanoscale, Molecular Pharmaceutics, [online], https://doi.org/10.1021/acs.molpharmaceut.1c00926, https://tsapps.nist.gov/publication/get_pdf.cfm?pub_id=933804 (Accessed December 17, 2024)