Targeting mitochondrial dynamics to overcome therapeutic resistance

Abstract

Mitochondria are frequently described as the powerhouse of the cell for apparent reasons. However, these organelles are dynamic was not known until recently. Scientists have found that mitochondria must undergo well-organized cycles of fragmentation/fission and fusion to maintain structural integrity, size, and distribution. These fission and fusion events are collectively called “mitochondrial dynamics” and are considered crucial for regulating organelle function. Mitochondrial fission accounts for the division of one mitochondrion into two. It is regulated by GTPase dynamin-related protein 1 (DRP1) and its adaptor proteins such as mitochondrial fission protein 1 (FIS1), mitochondrial fission factor (MFF), and mitochondrial dynamics protein of 49 and 51 kDa (Mid49, Mid51). DRP1, a cytosolic protein, is recruited to mitochondria to cause fragmentation upon activation through upregulation of serine 616 and downregulation of serine 637 phosphorylation. In contrast, mitochondrial fusion involves the fusion of two separate small mitochondria into one large mitochondrion, thereby generating a network of elongated or tubular mitochondria. These fusion events are regulated by GTPase dynamin-like proteins located on the outer (Mitofusin 1, MFN1 and mitofusin 2, MFN2) and inner (optic atrophy protein 1, OPA1) mitochondrial membrane. Fission is generally coupled with apoptosis, while fusion is associated with pro-survival signals. However, cancer cells can utilize mitochondrial dynamics, depending on their cellular state; this is reflected in the current conflicting literature explaining mitochondrial fission or fusion influencing tumor progression. Nonetheless, alterations in mitochondrial dynamics have been implicated as one of the key factors in tumor progression and therapeutic resistance across a wide spectrum of cancers. As a result, targeting mitochondrial dynamics is emerging as a potential strategy for solid tumors.