Small molecule inhibitors of mitochondrial division: tools that translate basic biological research into medicine

Abstract

Mitochondria do not exist as discrete static entities; rather, mitochondria form a network that continuously moves, divides, and fuses. The structure of this dynamic network is in part maintained by a balance of division and fusion events (Hoppins et al., 2007). The ratio of division to fusion events that defines a proper balance is not universal but varies with developmental stage, cell type, and biological circumstances. This is evident throughout the cell cycle in higher eukaryotes, where mitochondria elongate during the G1/S transition and fragment at the onset of mitosis, and when mitochondria fragment in response to certain cellular stimuli, such as increases in cytosolic calcium levels (Breckenridge et al., 2003; Cereghetti et al., 2008; Han et al., 2008; Mitra et al., 2009; Taguchi et al., 2007). The functional state and distribution of mitochondria are clearly influenced by its steady-state structure. When the normal balance of division and fusion is disrupted as a consequence of the inappropriate stimulation or inhibition of either process, problems arise at the cellular level that compromises the well-being of the organism as a whole. This is evident by the ever-increasing number of diseases in which abnormal mitochondrial dynamics have been etiologically implicated. In this context, the mitochondrial division and fusion machines are valuable and interesting targets of small molecule effectors, as inhibition or activation of these processes may be able to restore the proper dynamic balance and function. A small molecule inhibitor of mitochondrial division, mdivi-1, has already been identified and characterized (Cassidy-Stone et al., 2008). This inhibitor has provided valuable insight into the mechanism of mitochondrial division and has shown great therapeutic promise in a wide array of disease models. This review will focus on small molecule effectors of mitochondrial division, discussing their value in basic biological research as well as their therapeutic potential.

Figure 1

Modulation of Drp1-mediated mitochondrial division and potentiation of apoptosis by negative and positive effectors. Negative effectors may block Drp1 assembly, as is the case for mdivi-1, or other critical aspects of Drp1 function and thus attenuate mitochondrial division and/or mitochondrial outer membrane permeabilization (MOMP). Positive effectors may stimulate Drp1 assembly and/or function, and depending on the distinct set of effectors, which are likely defined by biological circumstances, mitochondrial division and/or MOMP can be stimulated.