A Mutation in the Mitochondrial Fission Gene Dnm1l Leads to Cardiomyopathy

Abstract

Mutations in a number of genes have been linked to inherited dilated cardiomyopathy (DCM). However, such mutations account for only a small proportion of the clinical cases emphasising the need for alternative discovery approaches to uncovering novel pathogenic mutations in hitherto unidentified pathways. Accordingly, as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen, we identified a mouse mutant, Python, which develops DCM. We demonstrate that the Python phenotype is attributable to a dominant fully penetrant mutation in the dynamin-1-like (Dnm1l) gene, which has been shown to be critical for mitochondrial fission. The C452F mutation is in a highly conserved region of the M domain of Dnm1l that alters protein interactions in a yeast two-hybrid system, suggesting that the mutation might alter intramolecular interactions within the Dnm1l monomer. Heterozygous Python fibroblasts exhibit abnormal mitochondria and peroxisomes. Homozygosity for the mutation results in the death of embryos midway though gestation. Heterozygous Python hearts show reduced levels of mitochondria enzyme complexes and suffer from cardiac ATP depletion. The resulting energy deficiency may contribute to cardiomyopathy. This is the first demonstration that a defect in a gene involved in mitochondrial remodelling can result in cardiomyopathy, showing that the function of this gene is needed for the maintenance of normal cellular function in a relatively tissue-specific manner. This disease model attests to the importance of mitochondrial remodelling in the heart; similar defects might underlie human heart muscle disease.

Dynamin-related Protein 1 Oligomerization in Solution Impairs Functional Interactions with Membrane-anchored Mitochondrial Fission Factor

“…When the proper balance of mitochondrial dynamics is disrupted, mitochondrial dysfunction is observed (1,2). This insult is associated with increased cell death in several human diseases, including neurodegenerative disorders (3,4), ischemiareperfusion injury (5,6), and glaucoma (7). Therefore, mitochondrial division has developed into a compelling therapeutic target for intervention with small molecule and peptide inhibitors that limit cell death in several of these pathologies (8 -13).…”

Mitofilin complexes: conserved organizers of mitochondrial membrane architecture

“…The membrane fusion GTPases OPA1 and mitofusin 2 (MFN2) are frequently found mutated in cases of dominant optic atrophy (DOA) and Charcot-MarieTooth disease type 2A, respectively, two distinct types of neuropathies (Alexander et al , 2000 ;Delettre et al , 2000 ;Z ü chner et al, 2004 ;Chen and Chan , 2006 ;Olichon et al , 2006 ;Chen et al , 2007 ;Feely et al , 2011 ) . Mutations affecting the mitochondrial fission factor dynamin-related protein 1 (DRP1) are connected to cardiomyopathy and to a neonatal lethal case of multisymptomatic disease with microencephaly and optic atrophy (Detmer and Chan , 2007 ;Waterham et al , 2007 ;Ashrafian et al , 2010 ;Westermann , 2010 ). The connection between fusion/fission proteins and the pathogenesis of the diseases is not fully understood.…”

Mitochondrial Dynamism and Cardiac Fate

“…Indeed, an increasing number of natural and experimental cardiomyopathies are being attributed to an imbalance in mitochondrial fusion/fission. The DCM of the Python mouse, created by ENU mutagenesis, is caused by a mutation in the mitochondrial fission factor Drp1/Dnm1l, 46 and a form of heritable bovine DCM is caused by a mutation in the fusion factor Opa3. 47, 48 Two recent independent reports describe cardiomyopathy and mitochondrial dysfunction in mice having only one functional Opa1 allele (Opa +/-).…”