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A Screen Using iPSC-Derived Hepatocytes Reveals NAD+ as a Potential Treatment for mtDNA Depletion Syndrome. Cell Rep 2018 Nov 06;25(6):1469-1484.e5

Date

11/08/2018

Pubmed ID

30404003

Pubmed Central ID

PMC6289059

DOI

10.1016/j.celrep.2018.10.036

Scopus ID

2-s2.0-85055754131 (requires institutional sign-in at Scopus site)   38 Citations

Abstract

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.

Author List

Jing R, Corbett JL, Cai J, Beeson GC, Beeson CC, Chan SS, Dimmock DP, Lazcares L, Geurts AM, Lemasters JJ, Duncan SA

Author

Aron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

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