Cell - 8 September 2016

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