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Investigating the Function of Crif1 in Cardiomyocytes Using Conditional Knockout Mouse Models

Investigating the Function of Crif1 in Cardiomyocytes Using Conditional Knockout Mouse Models
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Mitochondria are dynamic, energy producing cellular compartments involved in diverse physiological and pathological conditions. Recent studies have identified novel mitochondrial proteins, but the function of many of mitochondrial proteins remains uncharacterized. Crif1, which had been recognized as a nuclear localized transcriptional co-activator, was recently identified as a mitochondrial protein. Crif1 interacts with the large subunit of the mitochondrial ribosome, and is indispensable for the mitochondrial translation and membrane insertion of respiratory subunits. To elucidate the function of Crif1 in mitochondria and its physiological relevance, Crif1f/f mice were crossed with Myh6-cre/Esr1 transgenic mice, which harbor cardiomyocyte-specific Cre activity in a tamoxifen-dependent manner. The tamoxifen injections were given at six weeks postnatal, and the mutant mice survived only five months due to hypertrophic heart failure. In the mutant cardiac muscles, mitochondrial mass dramatically increased, while the inner structure was altered with lack of cristae. Mutant cardiac muscles showed decreased rates of oxygen consumption and ATP production, suggesting that Crif1 plays a critical role in the maintenance of both mitochondrial structure and respiration in cardiac muscles. Crif1 was also ablated in neonatal cardiac muscle by using Ckmm-cre transgenic line. In accordance with the phenotypes of Myh6-cre/Esr1
Crif1f/f mice, Ckmm-cre
Crif1f/f mice exhibited cardiac hypertrophy associated with mitochondrial dysfunction. The Ckmm-cre
Crif1f/f mice showed less severe hypertrophy but early death whereas Myh6-cre/Esr1
Crif1f/f mice exhibited a gradual course of hypertrophy and longer survival. I suggest Ckmm-cre
Crif1f/f mice and Myh6-cre/Esr1
Crif1f/f mice as new animal models for mitochondrial cardiomyopathy of young and adult onset, respectively.
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