Mitocans Induce Lipid Flip-Flop and Permeabilize the Membrane to Signal Apoptosis

Published

June 6, 2023

Author(s)

Stuart R. Castillo, Michael H. Nguyen, Mitchell DiPasquale, Elizabeth Kelley, Drew Marquardt

Abstract

Pancratistatin (PST) and narciclasine (NRC) are natural therapeutic agents which exhibit specificity towards the mitochondria of cancerous cells and initiate apoptosis. Unlike traditional cancer therapeutic agents, PST and NRC are effective, targeted, and have limited adverse effects on neighbouring healthy, non-cancerous cells. Currently, the mechanistic pathway of action for PST and NRC remains elusive, which in part inhibits PST and NRC from becoming efficacious therapeutic alternatives. Herein, we use neutron and X-ray scattering in combination with calcein-leakage assays to characterize the effects of PST, NRC, and Tamoxifen (TAM) on a biomimetic model membrane. We report an increase in lipid flip-flop half-times (t1/2) (≈ 12.03 %, ≈ 35.06 %, and a decrease of ≈ 45.72 %) with 2 mole percent PST, NRC, and TAM respectively. An increase in bilayer thickness (≈ 6.25 %, ≈ 7.81 %, and ≈ 7.81 %) with 2 mole percent PST, NRC, and TAM respectively. Lastly, an increase in membrane leakage (≈ 31.69 %, ≈ 37.00 %, and ≈ 34.37 %) with 2 mole percent PST, NRC, and TAM respectively. Considering the maintenance of an asymmetric lipid composition across the outer mitochondrial membrane (OMM) is crucial to eukaryotic cellular homeostasis and survival, our results suggest PST and NRC play a significant role in disrupting the native distribution of lipids within the OMM. A mechanism of action for PST and NRC induced mitochondrial apoptosis is proposed via the redistribution of the native OMM lipid organization and through OMM permeabilization.

Citation

Biophysical Journal

Volume

122

Issue

11

Pub Type

Journals

Download Paper

DOI Link

Keywords

lipid membranes, mitochondria, mitocans, flip-flop, permeabilization, small angle neutron scattering

Citation

Castillo, S. , Nguyen, M. , DiPasquale, M. , Kelley, E. and Marquardt, D. (2023), Mitocans Induce Lipid Flip-Flop and Permeabilize the Membrane to Signal Apoptosis, Biophysical Journal, [online], https://dx.doi.org/10.1016/j.bpj.2023.03.039 (Accessed May 1, 2024)