Ophiobolin A Covalently Targets Mitochondrial Complex IV Leading to Metabolic Collapse in Cancer Cells

Ophiobolin
A (OPA) is a sesterterpenoid fungal natural product
with broad anticancer activity. While OPA possesses multiple electrophilic
moieties that can covalently react with nucleophilic amino acids on
proteins, the proteome-wide targets and mechanism of OPA remain poorly
understood in many contexts. In this study, we used covalent chemoproteomic
platforms to map the proteome-wide reactivity of the OPA in a highly
sensitive lung cancer cell line. Among several proteins that OPA engaged,
we focused on two targets: lysine-72 of cytochrome c oxidase subunit
5A (COX5A) and cysteine-53 of mitochondrial hypoxia induced gene 1
domain family member 2A (HIGD2A). These two subunit proteins are part
of complex IV (cytochrome C oxidase) within the electron transport
chain and contributed significantly to the antiproliferative activity
of OPA. OPA activated mitochondrial respiration in a COX5A- and HIGD2A-dependent
manner, leading to an initial spike in mitochondrial ATP and heightened
mitochondrial oxidative stress. OPA compromised mitochondrial membrane
potential, ultimately leading to ATP depletion. We have used chemoproteomic
strategies to discover a unique anticancer mechanism of OPA through
activation of complex IV leading to compromised mitochondrial energetics
and rapid cell death.