Figure 1. Mitochondrial Therapeutic Targets Undergoing Evaluation in Trials and Their Proposed Mechanism of Action.

This figure is a schematic of a mitochondrion, including a generalized representation of the highlighted therapeutic targets and each of their proposed mechanism of action. The mechanisms of action and selected clinical outcomes are more fully discussed in this review, and selected clinical trials evaluating these therapies are summarized in Table 1 and Table 2. A) CPI-613 inhibits two major mitochondrial enzyme complexes in the TCA cycle, (KGDH) and pyruvate dehydrogenase (PDH).B) DCA (Dichloroacetate) inhibits pyruvate dehydrogenase kinase (PDK), thus activating pyruvate dehydrogenase (PDH) leading to glucose oxidation. C)ME-344 directly targets complex I of OXPHOS. D) Venetoclax is a BH3 mimetic that inhibits BCL2, an anti-apoptotic protein. E) Birinapant, LCL 161, and Debio 1143 are SMAC mimetics which bind to inhibitors of apoptosis which, in turn, enable tumor cell apoptosis. F) ONC201’s mechanism of action is not fully understood, but it has been shown to deplete mitochondrial DNA and disrupt ATP production. G) Minnelide is a water-soluble prodrug of triptolide, a potent heatshock protein (HSP) 70 inhibitor, which releases triptolide into the blood stream to slow tumor growth. H) IACS 10759 is a selective inhibitor of OXPHOS.

Abbreviations: BAK BCL2-antagonist/killer, BAX BCL2-associated X protein, BCL2 B-cell lymphoma 2, BH3 Bcl-2 Homology 3, DCA Dichloroacetate, Delta psi m mitochondrial membrane potential, DRP1 Dynamin-related protein 1, KDGH α-ketoglutarate dehydrogenase, mtDNA Mitochondrial DNA, OPA1 Optic atrophy 1, PDH Pyruvate dehydrogenase, SIRT3 Sirtuin-3 mitochondrial NAD-dependent deacetylase, SMAC Second mitochondria-derived activator of caspase, XIAP X-linked inhibitor of apoptosis.