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And Cell-Type–Specific Manifestations of Heteroplasmic Mtdna Tissue- and cell-type–specific manifestations of PNAS PLUS heteroplasmic mtDNA 3243A>G mutation in human induced pluripotent stem cell-derived disease model Riikka H. Hämäläinena, Tuula Manninena, Hanna Koivumäkia, Mikhail Kislinb, Timo Otonkoskia, and Anu Suomalainena,c,1 aResearch Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00280, Helsinki, Finland; bNeuroscience Center, University of Helsinki, 00790, Helsinki, Finland; and cDepartment of Neurology, Helsinki University Central Hospital, 00290, Helsinki, Finland Edited* by Gottfried Schatz, University of Basel, Reinach, Switzerland, and approved August 7, 2013 (received for review June 19, 2013) Mitochondrial DNA (mtDNA) mutations manifest with vast clinical tissues suggest that RC complexes are differentially affected even heterogeneity. The molecular basis of this variability is mostly in different tissues of one individual with m.3243A>G mutation unknown because the lack of model systems has hampered with the CI deficiency dominating (15). Induction of nuclear- mechanistic studies. We generated induced pluripotent stem cells encoded CII, succinate dehydrogenase (SDH), and mitochon- from patients carrying the most common human disease mutation drial accumulations in muscle and neurons are other typical > in mtDNA, m.3243A G, underlying mitochondrial encephalomyop- findings in RC deficiencies (16, 17), thought to be compensatory athy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. to the RC defect. The basis of the tissue-specific variability in RC During reprogramming, heteroplasmic mtDNA showed bimodal seg- manifestations is unknown. regation toward homoplasmy, with concomitant changes in mtDNA Defects in different mt-tRNAs have gene-specific clinical man- organization, mimicking mtDNA bottleneck during epiblast specifi- tRNA-Leu(UUR) – ifestations: associated with MELAS or MIDD, cation. Induced pluripotent stem cell derived neurons and various tRNA-Lys tRNA-Ser fi with myoclonic epilepsy, with deafness, and tissues derived from teratomas manifested cell-type speci crespira- tRNA-Ile fi with cardiomyopathies (5). Only sometimes the mani- tory chain (RC) de ciency patterns. Similar to MELAS patient tissues, CELL BIOLOGY complex I defect predominated. Upon neuronal differentiation, festations overlap, indicating that the pathological mechanisms complex I specifically was sequestered in perinuclear PTEN-induced have to extend beyond tRNA functions in mitochondrial trans- putative kinase 1 (PINK1) and Parkin-positive autophagosomes, sug- lation. These mechanisms, however, are unknown. This is largely gesting active degradation through mitophagy. Other RC enzymes because of the unsuccessful attempts to introduce exogenous showed normal mitochondrial network distribution. Our data show DNA to mitochondria, which has prevented generation of in vivo that cellular context actively modifies RC deficiency manifesta- disease models. Heteroplasmic mice carrying two normal mtDNA tion in MELAS and that autophagy is a significant component of variants (18) or randomly occurring mutations isolated from so- neuronal MELAS pathogenesis. matic tissues (19–22) have been generated by cytoplast fusion to zygotes. Further, random mtDNA mutagenesis has been induced mitochondria | disease modeling by manipulating nuclear-encoded mtDNA maintenance genes (23–26). However, transgenic mice, carrying human disease-asso- itochondrial DNA (mtDNA) mutations cause a mitochon- ciated mt-tRNA mutations, do not exist. Experimental models for Mdrial respiratory chain (RC) disease in 1:5,000 individuals mt-tRNA mutations would be needed because of their common in Western populations (1), and 1:200 of newborns carries a po- tentially pathogenic mtDNA mutation (2). After the original Significance description of the first mtDNA mutations (3, 4), more than 200 disease-causing mtDNA point mutations have been reported to Mitochondrial DNA (mtDNA) mutations are a common cause of underlie mitochondrial disease (5). The manifestations of these human inherited diseases and manifest with exceptional clini- diseases vary from infantile multisystem disorders to adult-onset cal heterogeneity and tissue specificity, the molecular basis of myopathies, cardiomyopathies, sensory organ failure, and neu- which are largely unknown. We produced induced pluripotent rodegeneration; indeed, mitochondrial disease can occur in any stem cells (iPSCs) from patients carrying the most common organ system, with any age of onset (5). A typical feature of mtDNA mutation, m.3243A>G. During reprogramming, the pathogenic mtDNA mutations is heteroplasmy: patient cells cells underwent an mtDNA bottleneck, mimicking that in epi- carry both normal and mutant mtDNA. Furthermore, the blast specification. We differentiated iPSCs to heteroplasmic threshold amount of mutant mtDNA manifesting as RC de- fi human cells and tissues with isogenic nuclear background and ciency and disease can vary between tissues and individuals, show that the disease manifestation depends on cellular con- contributing to high clinical variability (5). text. We show that upon neuronal differentiation, complex I is The heteroplasmic m.3243A>G transition in the transferRNA- Leucine(UUR) actively degraded by an autophagy-mediated mechanism. Our gene is the most common mtDNA mutation (6), data indicate that cellular context actively modifies mtDNA seg- varying from adult population frequency of 1:6,000 in Finland to regation and manifestations, and that complex I is actively down- prevalence of 1:424 in Australia (7, 8). This mutation most regulated in neurons with m.3243A>G mutation. commonly results in maternally inherited diabetes and deafness (MIDD) (9), but in other families it may manifest as cardiomy- Author contributions: R.H.H. and A.S. designed research; R.H.H., T.M., H.K., M.K., and T.O. opathy, or mitochondrial encephalomyopathy, lactic acidosis, performed research; R.H.H., M.K., and A.S. analyzed data; and R.H.H. and A.S. wrote and stroke-like episodes (MELAS) (6, 10–12). Despite common the paper. genetic background, the m.3243A>G mutation results in variable The authors declare no conflict of interest. forms of mitochondrial RC deficiency in different patients. By *This Direct Submission article had a prearranged editor. far the most common finding in MELAS is complex I (CI) de- 1To whom correspondence should be addressed. E-mail: anu.wartiovaara@helsinki.fi. fi fi ciency, whereas some patients have combined de ciencies This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. of the RC CI, CIII, and CIV (13, 14). Evidence from autopsy 1073/pnas.1311660110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1311660110 PNAS Early Edition | 1of9 Downloaded by guest on September 27, 2021 occurrence in patients, highly tissue-specific phenotypes, and un- iPSCs (Fig. S1A), and all MELAS lines showed expression of known mechanisms beyond mitochondrial translation. pluripotency markers (Fig. 1 B and C), silencing of the viral We report here reprogramming of heteroplasmic patient transgenes (Fig. 1D), and similar growth characteristics as the fibroblasts to induced pluripotent stem cells (iPSCs) and pro- control cells. Karyotypes of the four analyzed patient iPSC lines duction of heteroplasmic differentiated cell- and tissue types to were normal diploid (Fig. S1B). These results indicate that generate experimental models for mtDNA 3243A>G mutation m.3243A>G mutation did not affect reprogramming efficiency underlying MELAS and MIDD and report excellent replication of or iPSC genomic stability. findings in patient tissues with clues to pathogenic mechanisms. Three lines with high mutation load (>80% of total mtDNA; “MELAS-high”), three nearly homoplasmic wild-type lines Results (“MELAS-low”), and two control lines, one per control individual, Generation of iPSCs with Heteroplasmic mtDNA 3243A>G MELAS were chosen for further analysis. The biphasic segregation of the Mutation. We reprogrammed three patient and two control fi- heteroplasmic mutant mtDNA provided us an ideal isogenic set- broblast lines to iPSCs using retroviral vectors expressing Oct4, ting: identical nuclear background, but variable heteroplasmy Klf4, Sox2, and c-Myc (27). Patient line M1 was from a 39-y-old levels of mutant mtDNA, with the potential differences between man with MIDD, line M2 from a 52-y-old man with MIDD and the lines being attributes of mtDNA genotype. ataxia, and line M3 from a 55-y-old woman with cardiomyopathy. The MELAS-high iPSC lines produced well-differentiated Control (Ctr) lines were from healthy voluntary individuals (Ctr1 teratomas in immune-compromised mice (MELAS-high n =2; from a 48-y-old woman; Ctr2 from a 22-y-old woman). The MELAS-low n = 2) with tissues from all three germ layers, similar mutant mtDNA contents of the patients’ skeletal muscle were to other lines with healthy mitochondria (Fig. 1E). All lines 73, 50, and 90%, and of their fibroblasts 22, 21, and 35%, re- (MELAS-high n =3;MELAS-lown =3;controln = 2) differ- spectively. All cells were cultured with uridine supplementation entiated also in vitro to microtubule-associated protein 2 (MAP2) in pyruvate-containing growth medium to enable growth of RC- and βIII-tubulin–positive neurons and glial fibrillary acidic protein deficient cells (28). All fibroblast lines produced iPSC clones (GFAP)-positive glia (Fig. 1F). Cytosolic-free calcium imaging with normal embryonic stem (ES) cell-like morphology with showed that similar proportions of the differentiated neuronal
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