Mouse models for mtDNA mutation
| Model | Experimental manipulation | Phenotype | References |
| mtDNA point mutation | |||
| Mutator mouse (POLGA D257A) | Knockin modification of DNA polymerase γ exonuclease domain | Impaired respiratory chain function, premature aging phenotypes | Trifunovic et al., 2004; Kujoth et al., 2005 |
| Trans-mitochondrial mice (CAPR) | Cytoplasmic transfer of chloramphenicol-resistant mtDNAs to ES cells | Growth retardation, myopathy, cardiomyopathy | Marchington et al., 1999; Sligh et al., 2000 |
| Trans-mitochondrial mouse (T6589C) | Cytoplasmic transfer of mtDNA with T6589C missense mutation to ES cells | Impaired respiratory chain function, growth retardation | Kasahara et al., 2006 |
| Trans-mitochondrial mouse (T6589C + 13885insCdelT) | Cytoplasmic transfer of mtDNA with T6589C, 13885insC, and 13885insCdelT mutation to ES cells | Decreased complex IV activity, myopathy, cardiomyophathy | Fan et al., 2008 |
| mtDNA deletion | |||
| Trans-mitochondrial mouse (ΔmtDNA4696) | Cytoplasmic transfer of deleted mtDNA (Δ7,759–12,454) to pronuclear stage embryo | Impaired respiratory chain function, renal failure, early mortality | Inoue et al., 2000 |
| Deletor mouse (Twinkle dup353–365) | Transgenic expression of mutant mtDNA helicase twinkle | Progressive decrease of respiratory chain function | Tyynismaa et al., 2005 |
| Mito-PstI mouse | Skeletal muscle–specific expression of mitochondrially targeted PstI restriction endonuclease | Impaired respiratory chain function in skeletal muscle, myopathy | Srivastava and Moraes, 2005 |
| mtDNA depletion | |||
| TFAM−/− | Knockout of TFAM in whole body | Respiratory chain deficiency, embryonic lethality | Larsson et al., 1998 |
| TFAM−/− heart | Knockout of TFAM in cardiomyocyte | Dilated cardiomyopathy | Wang et al., 1999 |
| TFAM−/− forebrain neuron | Knockout of TFAM in forebrain | Neurodegenerative symptoms | Sörensen et al., 2001 |
| TFAM−/− dopaminergic neuron | Knockout of TFAM in dopaminergic neuron | Parkinson’s disease symptoms | Ekstrand et al., 2007 |
| TFAM−/− pancreatic β cell | Knockout of TFAM in pancreatic β cell | Mitochondrial diabetes | Silva et al., 2000 |
| POLGA−/− | Knockout of POLGA | Respiratory chain deficiency, embryonic lethality | Hance et al., 2005 |
| MFN1−/− + MFN2−/− skeletal muscle | Skeletal muscle–specific knockout of MFN1 and MFN2, GTPases essential for mitochondrial fusion | Respiratory chain deficiency in skeletal muscle, muscle atrophy, early mortality | Chen and Chan, 2010 |
| TK2−/− | Knockout of thymidine kinase 2 (TK2) | Growth retardation, early mortality | Zhou et al., 2008 |
| TK2 H126N | Knockin modification of TK2 found in human mtDNA depletion syndrome patients (TK2 H126N) | Impaired respiratory chain function in brain, growth retardation, early mortality | Akman et al., 2008 |
| RRM2B−/− | Knockout of RRM2B gene, encoding p53-controlled ribonucleotide reductase (p53R2) | Growth retardation, renal failure, muscle atrophy, early mortality | Bourdon et al., 2007; Kimura et al., 2003 |
| RNASEH1−/− | Knockout of mitochondrial ribonuclease H1 (RNaseH1) | Embryonic lethality, respiratory chain deficiency | Cerritelli et al., 2003 |
| mtDNA increase | |||
| PAC-hTFAM | Transgenic expression of P1 artificial chromosome containing human TFAM | No apparent pathophysiology | Ekstrand et al., 2004 |
| TFAM-EGFP | Transgenic expression of TFAM-EGFP fusion protein | Improve mitochondrial disease phenotypes | Nishiyama et al., 2010 |
| CAG-hTFAM | Transgenic expression of mouse TFAM cDNA under CAG promoter | Improve cardiac failure after myocardial infarction, delay neuronal cell death | Ikeuchi et al., 2005; Hokari et al., 2010 |
| TWINKLE | Transgenic expression of mouse TWINKLE cDNA | No apparent pathophysiology | Tyynismaa et al., 2004 |
| Twinkle + hTFAM | Transgenic expression of mouse TWINKLE cDNA and human TFAM cDNA | Progressive respiratory chain dysfunction | Ylikallio et al., 2010 |
| Model | Experimental manipulation | Phenotype | References |
| mtDNA point mutation | |||
| Mutator mouse (POLGA D257A) | Knockin modification of DNA polymerase γ exonuclease domain | Impaired respiratory chain function, premature aging phenotypes | Trifunovic et al., 2004; Kujoth et al., 2005 |
| Trans-mitochondrial mice (CAPR) | Cytoplasmic transfer of chloramphenicol-resistant mtDNAs to ES cells | Growth retardation, myopathy, cardiomyopathy | Marchington et al., 1999; Sligh et al., 2000 |
| Trans-mitochondrial mouse (T6589C) | Cytoplasmic transfer of mtDNA with T6589C missense mutation to ES cells | Impaired respiratory chain function, growth retardation | Kasahara et al., 2006 |
| Trans-mitochondrial mouse (T6589C + 13885insCdelT) | Cytoplasmic transfer of mtDNA with T6589C, 13885insC, and 13885insCdelT mutation to ES cells | Decreased complex IV activity, myopathy, cardiomyophathy | Fan et al., 2008 |
| mtDNA deletion | |||
| Trans-mitochondrial mouse (ΔmtDNA4696) | Cytoplasmic transfer of deleted mtDNA (Δ7,759–12,454) to pronuclear stage embryo | Impaired respiratory chain function, renal failure, early mortality | Inoue et al., 2000 |
| Deletor mouse (Twinkle dup353–365) | Transgenic expression of mutant mtDNA helicase twinkle | Progressive decrease of respiratory chain function | Tyynismaa et al., 2005 |
| Mito-PstI mouse | Skeletal muscle–specific expression of mitochondrially targeted PstI restriction endonuclease | Impaired respiratory chain function in skeletal muscle, myopathy | Srivastava and Moraes, 2005 |
| mtDNA depletion | |||
| TFAM−/− | Knockout of TFAM in whole body | Respiratory chain deficiency, embryonic lethality | Larsson et al., 1998 |
| TFAM−/− heart | Knockout of TFAM in cardiomyocyte | Dilated cardiomyopathy | Wang et al., 1999 |
| TFAM−/− forebrain neuron | Knockout of TFAM in forebrain | Neurodegenerative symptoms | Sörensen et al., 2001 |
| TFAM−/− dopaminergic neuron | Knockout of TFAM in dopaminergic neuron | Parkinson’s disease symptoms | Ekstrand et al., 2007 |
| TFAM−/− pancreatic β cell | Knockout of TFAM in pancreatic β cell | Mitochondrial diabetes | Silva et al., 2000 |
| POLGA−/− | Knockout of POLGA | Respiratory chain deficiency, embryonic lethality | Hance et al., 2005 |
| MFN1−/− + MFN2−/− skeletal muscle | Skeletal muscle–specific knockout of MFN1 and MFN2, GTPases essential for mitochondrial fusion | Respiratory chain deficiency in skeletal muscle, muscle atrophy, early mortality | Chen and Chan, 2010 |
| TK2−/− | Knockout of thymidine kinase 2 (TK2) | Growth retardation, early mortality | Zhou et al., 2008 |
| TK2 H126N | Knockin modification of TK2 found in human mtDNA depletion syndrome patients (TK2 H126N) | Impaired respiratory chain function in brain, growth retardation, early mortality | Akman et al., 2008 |
| RRM2B−/− | Knockout of RRM2B gene, encoding p53-controlled ribonucleotide reductase (p53R2) | Growth retardation, renal failure, muscle atrophy, early mortality | Bourdon et al., 2007; Kimura et al., 2003 |
| RNASEH1−/− | Knockout of mitochondrial ribonuclease H1 (RNaseH1) | Embryonic lethality, respiratory chain deficiency | Cerritelli et al., 2003 |
| mtDNA increase | |||
| PAC-hTFAM | Transgenic expression of P1 artificial chromosome containing human TFAM | No apparent pathophysiology | Ekstrand et al., 2004 |
| TFAM-EGFP | Transgenic expression of TFAM-EGFP fusion protein | Improve mitochondrial disease phenotypes | Nishiyama et al., 2010 |
| CAG-hTFAM | Transgenic expression of mouse TFAM cDNA under CAG promoter | Improve cardiac failure after myocardial infarction, delay neuronal cell death | Ikeuchi et al., 2005; Hokari et al., 2010 |
| TWINKLE | Transgenic expression of mouse TWINKLE cDNA | No apparent pathophysiology | Tyynismaa et al., 2004 |
| Twinkle + hTFAM | Transgenic expression of mouse TWINKLE cDNA and human TFAM cDNA | Progressive respiratory chain dysfunction | Ylikallio et al., 2010 |
ES, embryonic stem.