Novel targets for mitochondrial medicine

Abstract

Mitochondria-classically viewed as the powerhouses of the cell-have taken center stage in disease pathogenesis and resolution. Mitochondrial dysfunction, which originates from primary defects within the organelle or is induced by environmental stresses, plays a critical role in human disease. Despite their central role in human health and disease, there are no approved drugs that directly target mitochondria. We present possible new druggable targets in mitochondrial biology, including protein modification, calcium ion (Ca(2+)) transport, and dynamics, as we move into a new era of mitochondrial medicine.

Fig. 1. Key players—and therapeutic targets—in mitochondrial protein modification, Ca²⁺ transport, and dynamics

Mitochondrial protein can be modified by the thioester–coenzyme A (CoA) produced by substrate metabolism, for example, acetyl-CoA, malonyl-CoA, succinyl-CoA. The most commonly studied is the acetylation of lysine residue (LysAc). The LysAc level is determined by the availability of acetyl-CoA and the activity of deacetylases, sirtuins, which catalyze deacetylation at the expenses of nicotinamide adenine dinucleotide (NAD⁺). Mitochondrial NAD⁺ level is regulated by the activities of tricarboxylic acid (TCA) cycle and oxidative phosphorylation. Nicotinamide (NAM) generated from deacetylation reaction is converted to nicotinamide mononucleotide (NMN) by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme. Alternatively, NMN is synthesized from nicotinamide riboside (NR) by nicotinamide riboside kinase (NRK). NMN is converted to NAD⁺ by nicotin-amide mononucleotide adenylyltransferase 3 (NMNAT3) in the mitochondria. Ca²⁺ is a key player in orchestrating metabolism and signaling function of the mitochondria. It is mainly stored in endoplasmic reticulum (ER) and transported into mitochondrial matrix by mitochondrial Ca²⁺ uniporter (MCU) to stimulate enzymes in TCA cycle and oxidative phosphorylation. Mitochondrial Ca²⁺ also triggers the opening of mPTP, which likely plays a physiological role in matrix Ca²⁺ release and a detrimental role in cell death. The mitochondrial dynamic regulatory proteins may bear new roles beyond fusion and fission. The outer membrane fusion protein mitofusin (MFN) tethers the mitochondria and ER membranes and through which facilitate mitochondrial Ca²⁺ uptake. The inner membrane fusion protein optic atrophy 1 (OPA1) controls the cristae structure and through which modulates mitochondrial respiratory chain activity. The fission protein dynamin-related protein 1 (DRP1) also regulates BAX (BCL2-associated X protein) and mPTP. The black arrows indicate potential targets for drug development.