Phenotypes associated with this allele

• Allele Symbol: Atpaf1^em1Cya
• Allele Name: endonuclease-mediated mutation 1, Cyagen Biosciences
• Allele ID: MGI:7792241
• Summary: 1 genotype

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Atpaf1^em1Cya/Atpaf1^em1Cya	involves: C57BL/6N	MGI:8163692

Genotype
MGI:8163692

hm1

• Allelic Composition: Atpaf1^em1Cya/Atpaf1^em1Cya
• Genetic Background: involves: C57BL/6N

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

growth/size/body

increased heart weight ( J:347150 )

• adult heart weight to tibia length ratio (HW/T, mg/mm) is significantly higher than in wild-type controls

cardiac hypertrophy ( J:347150 )

decreased body size ( J:347150 )

• both male and female mice are developmentally normal but grow to adulthood with smaller body sizes than wild-type controls

slow postnatal weight gain ( J:347150 )

• mice grow slower than wild-type controls with modestly decreased body weight after weaning and never attain a normal body weight at 25 weeks of age

homeostasis/metabolism

impaired autophagy ( J:347150 )

• cardiac protein levels of LC3-II (the lipidated form of LC3, a key marker for autophagosomes) are significantly decreased, indicating impaired mitochondrial autophagy in the heart

increased circulating lactate level ( J:347150 )

• at 25-30 weeks of age, but not earlier, mice show significantly higher plasma lactate levels than wild-type controls

abnormal enzyme/coenzyme level ( J:347150 )

• cardiac mitochondria show significantly reduced protein expression levels of dimeric, monomeric, and free F1, and decreased ATP synthase content relative to wild-type hearts

abnormal enzyme/coenzyme activity ( J:347150 )

• mitochondrial protein samples extracted from cardiac (left ventricular) tissue of 20-week-old mice show significantly reduced ATP5F1A (ATP synthase F1 subunit alpha, aka ATP5A) and ATP5F1B (ATP synthase F1 subunit beta, aka ATP5B) protein levels, indicating impaired assembly of the F1 component of ATP synthase

• cardiac mitochondria show a 40-65% decrease in mitochondrial ATP hydrolysis (ATPase) activity by in-gel ATPase staining, due to reduced dimerization and overall content of F1Fo-ATP synthase

cellular

abnormal myocardial fiber mitochondrial morphology ( J:347150 )

• at 15-18 weeks of age, TEM shows disorganized and smaller mitochondria with reduced cristae density and mitochondria area in the heart; vacuolization and swelling are observed

increased myocardial fiber apoptosis ( J:347150 )

• TUNEL assays show a significant increase in apoptotic cardiomyocytes; protein expression of cleaved Caspase3 is significantly higher than in wild-type hearts

abnormal mitochondrial crista morphology ( J:347150 )

• at 15-18 weeks of age, cardiac mitochondria show a significant reduction in the number of cristae per 1um²

decreased mitochondrial size ( J:347150 )

• at 15-18 weeks of age, single cardiac mitochondrial size is significantly smaller than in wild-type controls

dilated mitochondrion ( J:347150 )

• swelling of cardiac mitochondria is observed

impaired autophagy ( J:347150 )

• cardiac protein levels of LC3-II (the lipidated form of LC3, a key marker for autophagosomes) are significantly decreased, indicating impaired mitochondrial autophagy in the heart

abnormal cellular respiration ( J:347150 )

• routine respiration of cardiac mitochondria from 18-20-week-old mice is significantly reduced, as measured via concomitant addition of malate and pyruvate, indicating decreased basal mitochondrial respiration capacity

abnormal mitochondrial physiology ( J:347150 )

• cardiac mitochondria show a significantly reduced respiratory control ratio (RCR)

• increased oxidative stress contributes to a modest depolarization of cardiac mitochondria

• protein levels of OPA1 (optic atrophy 1) and MFN2 (mitofusin 2) are markedly reduced whereas those of DNM1L (dynamin 1 like, aka DRP1) are increased, indicating abnormal mitochondrial dynamics in the heart

• however, calcium-induced swelling rates of cardiac mitochondria are normal, as determined by mitochondrial permeability transition (MPT) pore activation

abnormal oxidative phosphorylation ( J:347150 )

• cardiac mitochondria show significantly reduced oxidative phosphorylation capacity of complex I (OXPHOS_CI) driven by the NADH-related substrates, as measured via concomitant addition of malate and pyruvate followed by ADP and glutamate

• when succinate is subsequently added, cardiac mitochondria show significantly decreased maximal OXPHOS capacity of complex I and complex II (OXPHOS_{CI+ CII})

• however, LEAK respiration (LEAK_CI+CII, i.e. mitochondrial respiration independent of ATP-production) and the maximal convergent non-phosphorylating respiration of the electron transport system (ETS_CI+CII) are not affected

abnormal mitochondrial ATP synthesis coupled electron transport ( J:347150 )

• cardiac mitochondria show a significantly reduced respiratory control ratio (RCR)

• in-gel CI-CIV activity staining on Blue Native (BN)-PAGE gels shows a significant reduction in complex I (CI) activity in heart samples

• however, in-gel CII and CIV activities are unaffected

oxidative stress ( J:347150 )

• frozen heart sections exhibit a marked increase in the % of DHE-positive nuclei, indicating increased superoxide production

• mRNA expression of Nox4 (NADPH oxidase 4) -- a superoxide related gene -- is significantly increased whereas expression of Gpx1 (glutathione peroxidase 1) -- a member of the antioxidant enzyme system -- is significantly decreased in ventricular heart tissue

cardiovascular system

abnormal myocardial fiber mitochondrial morphology ( J:347150 )

• at 15-18 weeks of age, TEM shows disorganized and smaller mitochondria with reduced cristae density and mitochondria area in the heart; vacuolization and swelling are observed

increased myocardial fiber size ( J:347150 )

• at 18-22 weeks of age, the cardiomyocyte cross-sectional area is significantly greater than in wild-type controls

increased heart weight ( J:347150 )

• adult heart weight to tibia length ratio (HW/T, mg/mm) is significantly higher than in wild-type controls

cardiac hypertrophy ( J:347150 )

cardiac fibrosis ( J:347150 )

• Massons trichrome staining shows a significant increase in cardiac fibrosis relative to wild-type controls

abnormal cardiovascular system physiology ( J:347150 )

• adult mice exhibit cardiac dysfunction, hypertrophy, and LV remodeling

dilated cardiomyopathy ( J:347150 )

• adult mice develop dilated cardiomyopathy

decreased heart left ventricle muscle contractility ( J:347150 )

• echocardiography of adult hearts shows a sustained decrease in left ventricular ejection fraction (EF%) and fractional shortening (FS%)

increased myocardial fiber apoptosis ( J:347150 )

• TUNEL assays show a significant increase in apoptotic cardiomyocytes; protein expression of cleaved Caspase3 is significantly higher than in wild-type hearts

congestive heart failure ( J:347150 )

• adult hearts show a significant increase in mRNA expression of Nppb (natriuretic peptide type B, aka Bnp) relative to wild-type hearts

muscle

abnormal myocardial fiber mitochondrial morphology ( J:347150 )

• at 15-18 weeks of age, TEM shows disorganized and smaller mitochondria with reduced cristae density and mitochondria area in the heart; vacuolization and swelling are observed

increased myocardial fiber size ( J:347150 )

• at 18-22 weeks of age, the cardiomyocyte cross-sectional area is significantly greater than in wild-type controls

dilated cardiomyopathy ( J:347150 )

• adult mice develop dilated cardiomyopathy

decreased heart left ventricle muscle contractility ( J:347150 )

• echocardiography of adult hearts shows a sustained decrease in left ventricular ejection fraction (EF%) and fractional shortening (FS%)

increased myocardial fiber apoptosis ( J:347150 )

• TUNEL assays show a significant increase in apoptotic cardiomyocytes; protein expression of cleaved Caspase3 is significantly higher than in wild-type hearts

behavior/neurological

behavior/neurological phenotype ( J:347150 )

N • mice show no overt signs of behavioral abnormalities