Structural Remodeling of Mitochondrial Membranes in Cancerous Colon Cells: Insights from Neutron Scattering and Lipidomics

Herein, we show compelling evidence of structural remodeling in mitochondrial membranes of cancerous colon cells when compared to their noncancerous counterparts. The physical characteristics of cancerous and noncancerous mitochondria were systematically investigated using small-angle neutron scattering (SANS), cryogenic electron tomography (cryo-ET), neutron spin-echo (NSE) spectroscopy, and high-throughput lipidomics. Our results exhibit evidence of both mechanical softening of the mitochondrial membrane, as seen by NSE, and ultrastructure rearrangements of the inner mitochondrial membranes, as seen by SANS and cryo-ET, in cancerous cells. These differences in properties seem to be correlated with changes in the lipidome, suggesting the changes are due to the limited number of lipid classes immediately available during the rapid proliferation of cancerous cells. Finally, we highlight a mechanism by which pancratistatin (PST), a natural anticancer therapeutic candidate, may selectively induce apoptosis by altering the mechanical properties and ultrastructure of cancerous mitochondria while sparing noncancerous mitochondria. Discovery of these structural anomalies will lead to improvements in diagnostics, therapeutic development, and the advancement of targeted approaches for traditionally complex cancers which evade our current treatments.