A Screen Using iPSC-Derived Hepatocytes Reveals NAD+ as a Potential Treatment for mtDNA Depletion Syndrome

Cell Rep. 2018 Nov 6;25(6):1469-1484.e5. doi: 10.1016/j.celrep.2018.10.036.


Patients with mtDNA depletion syndrome 3 (MTDPS3) often die as children from liver failure caused by severe reduction in mtDNA content. The identification of treatments has been impeded by an inability to culture and manipulate MTDPS3 primary hepatocytes. Here we generated DGUOK-deficient hepatocyte-like cells using induced pluripotent stem cells (iPSCs) and used them to identify drugs that could improve mitochondrial ATP production and mitochondrial function. Nicotinamide adenine dinucleotide (NAD) was found to improve mitochondrial function in DGUOK-deficient hepatocyte-like cells by activating the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). NAD treatment also improved ATP production in MTDPS3-null rats and in hepatocyte-like cells that were deficient in ribonucleoside-diphosphate reductase subunit M2B (RRM2B), suggesting that it could be broadly effective. Our studies reveal that DGUOK-deficient iPSC-derived hepatocytes recapitulate the pathophysiology of MTDPS3 in culture and can be used to identify therapeutics for mtDNA depletion syndromes.

Keywords: drug screen; iPSC-derived hepatocytes; inborn errors in hepatic metabolism; liver disease; mitochondrial disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Base Sequence
  • Cell Differentiation
  • Cell Respiration
  • DNA, Mitochondrial / genetics*
  • Female
  • Glucose / metabolism
  • Glycolysis
  • Hepatocytes / cytology
  • Hepatocytes / metabolism*
  • Hepatocytes / ultrastructure
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism*
  • Male
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Mutation / genetics
  • NAD / metabolism*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Rats
  • Ribonucleotide Reductases / metabolism
  • Syndrome


  • DNA, Mitochondrial
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • NAD
  • Adenosine Triphosphate
  • Ribonucleotide Reductases
  • Phosphotransferases (Alcohol Group Acceptor)
  • deoxyguanosine kinase
  • Glucose