ReviewDrug Discovery

Novel targets for mitochondrial medicine

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Science Translational Medicine  17 Feb 2016:
Vol. 8, Issue 326, pp. 326rv3
DOI: 10.1126/scitranslmed.aac7410


  • 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 nicotinamide 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.


  • Table 1. Selected clinical trials on drugs affecting mitochondrial function.

    Trial statuses were confirmed as of 26 January 2016. AMP, adenosine-5′-monophosphate.

    ClassCompound name
    AntioxidantMitoQROS scavengerChronic kidney
    disease (CKD)
    ResveratrolSIRT1 activatorCKD3CompletedNCT02433925
    EPI-743 (Edison
    Coenzyme Q10
    Rett syndrome2CompletedNCT01822249
    Idebenone (Santhera Pharmaceuticals)CoQ10-basedDuchenne
    3Positive (74)NCT01027884
    ROS scavenger
    Acute myocardial
    infarction (AMI)
    4Positive (75)NCT00265239
    ROS scavenger
    lateral sclerosis
    3Negative (76)NCT00330681
    CoQ10ROS scavengerParkinson’s
    3Negative (77)NCT00740714
    SS31 (bendavia)
    (Stealth BioTherapeutics Inc.)
    Metabolism modulatorAcipimoxNiacin derivativeObesity2Negative (78)NCT01488409
    MetforminType 1 diabetes4OngoingNCT01813929
    fatty liver disease
    CreatineMetabolismHuntington’s disease3TerminatedNCT00712426
    Acadesine (Merck
    Sharp & Dohme Corp.)
    protein kinase,
    Myocardial infarction3Negative (79)NCT00872001
    Mitochondrial permeability
    transition pore (mPTP)
    Cyclosporine ACyclophilin DAcute kidney injury2OngoingNCT02397213
    Cyclosporine ACyclophilin DAMI3Negative (46)NCT01502774
    Dimebon (Pfizer)UnknownAlzheimer’s disease3Negative (80)NCT00838110
    TRO40303 (Trophos)Mitochondrial
    AMI2Negative (81)NCT01374321

    *The compound entered a phase 4 trial on the basis that it is used as a nutritional supplement.

    †Results reported at the American College of Cardiology 2015 Scientific Sessions.

    ‡Terminated as unlikely to be effective.

    • Table 2. Potential new therapeutic targets in mitochondria.

      These new targets are shown in Fig. 1 and have been tested in preclinical studies.

      CompoundCompound typeTarget site or mechanismDiseaseReference
      NMNSmall moleculeNAD+, protein acetylationHeart failure, metabolic diseases,
      neurodegeneration, aging
      (22, 30, 32)
      NRSmall moleculeNAD+, protein acetylationMetabolic diseases, aging(24)
      P7C3 chemicalsSmall moleculeActivate NAMPTNeurodegeneration(31)
      HonokiolSmall moleculeActivate SIRT3Cardiac hypertrophy(82)
      Ru360Small moleculeMCUMyocardial infarction(38, 40)
      Cyclophilin D–specific
      Small moleculemPTPIschemic disease(8386)
      Mdivi-1Small moleculeDRP1Ischemic disease,
      (56, 87)
      S3Small moleculeMFNNeurodegeneration(57)
      P110Small peptideDRP1Neurodegeneration(55, 88)

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