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.

Pictolysin-III, a Hemorrhagic Type-III Metalloproteinase Isolated from Bothrops pictus (Serpentes: Viperidae) Venom, Reduces Mitochondrial Respiration and Induces Cytokine Secretion in Epithelial and Stromal Cell Lines

“…Finally, Pic-III is the first of the SVMPs reported with action on mitochondrial bioenergetics. Emergent evidence suggests that several snake venom toxin classes (e.g., phospholipases [ 92 , 109 ], thrombin-like enzymes [ 28 ], three-finger toxins [ 110 , 111 ]) act on the mitochondrial bioenergetics [ 3 ], exhibiting unique and novel mechanisms that are not yet fully understood. This highlights the mitochondrion as an essential player in the snake venom action that requires more studies.…”

“…Snake venoms are a natural source of active proteins, also known as toxins, with enzymatic (metalloproteinases, serineproteinases, phospholipases A2, and L-amino oxidases) or non-enzymatic (neurotoxins, disintegrins, C-type lectins, cytotoxins, myotoxins, and cardiotoxins) activities. Several of these toxins are multifunctional and may act on multiple protein targets of their preys, which are highly specific to disrupt several biological processes in human cells, including cancer cells [ 1 , 2 , 3 , 4 ]. A plethora of studies on human envenoming has shown the functional diversity of snake toxins [ 1 , 5 ]; however, molecular mechanisms of action of several of these biomolecules remain poorly studied.…”