evidence that upon neuronal differentiation, complex I was
actively sequestered into PINK-Parkin-positive autophago-
somes and degraded. This represented the first example of tis-
sue-specific changes in respiratory activity due to mtDNA
mutation and highlighted the power of patient-specific iPSCs
for modeling mitochondrial diseases. A third report by Kodaira
Table 2. iPSC Models of Mitochondrial Diseases and Inborn Errors of Metabolism
Disease Genetic Mutation Major Findings References
Diabetes mtDNA 3243A>G diPSC were obtained from patient cells
ddecreased mtDNA content during reprogramming
dbimodal segregation of mtDNA
Fujikura et al., 2012
PS mtDNA 2.5 kb deletion dspontaneous generation of mutation-free iPSCs
dreduced hematopoietic differentiation capacity of iPSCs with
high mutation load
Cherry et al., 2013
MELAS mtDNA 13513G>A dspontaneous generation of mutation-free iPSCs
dmtDNA mosaicism in starting population
dimpaired cardiac differentiation of iPSCs with high mutation load
Folmes et al., 2013
MELAS mtDNA 3243A>G dbimodal segregation of mtDNA
drecapitulation of respiratory defects upon differentiation into
multiple cell types
dneuron-specific sequestration of PINK-Parkin into autophagosomes
Ha ̈ma ̈la ̈inen et al., 2013
MELAS mtDNA 3243A>G dbimodal segregation of mtDNA
dcomplex I defect upon differentiation of iPSCs
Kodaira et al., 2015
MELAS mtDNA 5541C>T dspontaneous generation of disease-free iPSCs
dsignificant decrease in neuronal differentiation efficiency in
mutant iPSCs
dnormal differentiation into skeletal muscle
Hatakeyama et al., 2015
MELAS
LS
mtDNA 3243A>G
mtDNA 8993T>G
mtDNA 13513G>A
dbimodal segregation of mtDNA
ddecreased basal and maximum respiration, ATP turnover, and
oxidative reserve upon iPSC differentiation
dimpaired cardiac differentiation
dgeneration of disease-free iPSC by SCNT
Ma et al., 2014
Pompe
disease
mutations in GAA dultrastructural abnormalities and dysfunctional mitochondria
in Pompe iPSCs
dglycogen accumulation, mitochondrial dysfunction, and defects in
protein glycosylation in cardiomyocytes derived from Pompe iPSCs
Huang et al., 2011;
Raval et al., 2015
Danon
disease
mutations in LAMP-2 dcellular hypertrophy, defects in calcium handling, and increased
oxidative stress in cardiomyocytes derived from Danon iPSCs
drescue of disease phenotypes by LAMP-2 overexpression or
treatment with antioxidants
Hashem et al., 2015
Barth
syndrome
mutations in TAZ ddecreased levels of cardiolipin and mitochondrial dysfunction
in Barth iPSCs
dincrease in levels of reactive oxygen species in cardiomyocytes
derived from Barth iPSCs
drestoration of disease phenotypes by TAZ restoration
Wang et al., 2014b
Fabry
disease
mutations ina-GalA daccumulation of GL3 in lysosomes of cardiomyocytes derived
from Fabry iPSCs
damelioration of disease phenotypes by substrate reduction therapy
Itier et al., 2014
A1AT
deficiency
mutations in ATT daggregation of A1AT in hepatocytes derived from A1ATD iPSCs
ddisease-specific intracellular increase in A1AT polymers upon
treatment with MG132
Rashid et al., 2010
GSD-I mutations in
glucose-6-phospate
delevated lipid and glycogen accumulation in hepatocytes
differentiated from GSD-I iPSCs
dexpression of glucagon-responsive genes upon glucagon stimulation
Rashid et al., 2010
FH mutations in LDL
receptor
dabsence of LDL receptor in FH iPSCs
ddeficient LDL receptor-mediated cholesterol uptake in hepatocytes
derived from FH iPSCs
Rashid et al., 2010
PS, Pearson marrow pancreas syndrome; MELAS, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; LS, Leigh syn-
drome; GAA, acid alpha-glucosidase; LAMP-2, lysosomal-associated membrane protein type 2; TAZ, tafazzin;a-GalA,a-galactosidase A; GL3, globo-
triaosylceramide; A1AT, alpha-1 antitrypsin; GSD1, glycogen storage disease type Ia; FH, familial hypercholesterolemia; LDL, low-density lipoprotein.
Cell 166 , September 8, 2016 1379