An Emergent Role for Mitochondrial Bioenergetics in the Action of Snake Venom Toxins on Cancer Cells

Abstract

Beyond the role of mitochondria in apoptosis initiation/execution, some mitochondrial adaptations support the metastasis and chemoresistance of cancer cells. This highlights mitochondria as a promising target for new anticancer strategies. Emergent evidence suggests that some snake venom toxins, both proteins with enzymatic and non-enzymatic activities, act on the mitochondrial metabolism of cancer cells, exhibiting unique and novel mechanisms that are not yet fully understood. Currently, six toxin classes (L-amino acid oxidases, thrombin-like enzymes, secreted phospholipases A2, three-finger toxins, cysteine-rich secreted proteins, and snake C-type lectin) that alter the mitochondrial bioenergetics have been described. These toxins act through Complex IV activity inhibition, OXPHOS uncoupling, ROS-mediated permeabilization of inner mitochondrial membrane (IMM), IMM reorganization by cardiolipin interaction, and mitochondrial fragmentation with selective migrastatic and cytotoxic effects on cancer cells. Notably, selective internalization and direct action of snake venom toxins on tumor mitochondria can be mediated by cell surface proteins overexpressed in cancer cells (e.g. nucleolin and heparan sulfate proteoglycans) or facilitated by the elevated Δψm of cancer cells compared to that non-tumor cells. In this latter case, selective mitochondrial accumulation, in a Δψm-dependent manner, of compounds linked to cationic snake peptides may be explored as a new anti-cancer drug delivery system. This review analyzes the effect of snake venom toxins on mitochondrial bioenergetics of cancer cells, whose mechanisms of action may offer the opportunity to develop new anticancer drugs based on toxin scaffolds.

Keywords: OXPHOS (oxidative phosphorylation); anticancer compounds; cardiolipin; electron transport chain; migrastatics; mitochondrial dysfunction; snake venom.

Figure 1

Effects of snake toxins on mitochondrial bioenergetics in cancer cells. It is represented the mechanisms of action of thrombin-like enzymes (TLE), secreted Lys49- and Asp49-phospholipases A2 (PLA2), three-finger toxins (3FTx) and L-amino acid oxidases (LAAO). Some toxins affect the oxidative phosphorylation (OXPHOS) by uncoupling or Complex IV inhibition, which decreases the mitochondrial membrane potential (Δψ_m) and ATP levels. Moreover, other toxins produce mitochondrial fragmentation (e.g. TLE and 3FTx) or permeabilization of inner mitochondrial membrane (e.g. Asp49-PLA2 and LAAO), triggering apoptosis. Cysteine-rich secreted proteins, and snake C-type lectin toxins were excluded of this figure due to reduced information of a putative mechanism of action on mitochondria. OCR, oxygen consumption rate; Cyt. C, cytochrome C; mPTP, mitochondrial permeability transition pore; mtROS, mitochondrial ROS; AA, amino acids; mt-fission, mitochondrial fission.