ECSIT is a critical limiting factor for cardiac function

ECSIT is a protein with roles in early development, activation of the transcription factor NFB and production of mitochondrial reactive oxygen species (mROS) that facilitates clearance of intracellular bacteria like Salmonella. ECSIT is also an important assembly factor for mitochondrial complex I. Unlike the murine form of Ecsit (mEcsit), we demonstrate here that human ECSIT (hECSIT) to be highly labile. In order to explore if the instability of hECSIT affects functions previously ascribed to its murine counterpart, we created a novel transgenic mouse in which the murine Ecsit gene is replaced by the human ECSIT gene. The humanised mouse has low levels of hECSIT protein in keeping with its intrinsic instability. Whereas low level expression of hECSIT was capable of fully compensating for mEcsit in its roles in early development and activation of the NFB pathway, macrophages from humanised mice showed impaired clearance of Salmonella that was associated with reduced production of mROS. Notably, severe cardiac hypertrophy manifested in ageing humanised mice leading to premature death. The cellular and molecular basis to this phenotype is delineated by showing that low levels of human ECSIT protein leads to marked reduction in assembly and activity of mitochondrial complex I with impaired oxidative phosphorylation and reduced production of ATP. Cardiac tissue from humanised hECSIT mice also shows reduced mitochondrial fusion and more fission but impaired clearance of fragmented mitochondria. A cardiomyocyte-intrinsic role for Ecsit in mitochondrial function and cardioprotection is also demonstrated. We also show that cardiac fibrosis and damage in humans correlates with low expression of human ECSIT. In summary, our findings identify a new role for ECSIT in cardioprotection whilst also generating a valuable new experimental model to study mitochondrial dysfunction and cardiac pathophysiology.