EFHD1 causes metabolic liver injury by triggering Ca2+-dependent mitochondrial fission

The occurrence of metabolic liver disease is increasing globally. Multiple GWAS studies have found an association between elevated EFHD1 expression in the liver and markers for metabolic liver disease in diverse populations. EFHD1 is a calcium-sensing protein at the mitochondrial outer membrane and EFHD1 ablation has previously been shown to protect cardiac mitochondria. Here we utilize EFHD1 knockout (EFHD1-KO) models to assess whether EFHD1 represents a novel therapeutic target to treat metabolic liver disease. We found that EFHD1-KO mice exposed to diet-induced metabolic liver disease exhibited significant decreases in liver disease markers which correlated to lower levels of liver inflammation and fibrosis, when compared with control animals. This effect was also observed when EFHD1 was knocked down in the liver using a virus. On the cellular level, when comparing to wild-type cells, we found that EFHD1-KO cells exhibited significantly elongated mitochondria which were highly resistant to calcium-induced mitochondrial fission. Moreover, we observed significantly lower levels of mitochondrial dsRNA in diseased cells lacking EFHD1 which corresponded to lower expression levels of proteins associated with the integrated stress response (ISR). The ISR can be triggered by mitochondrial dsRNA release, resulting in hepatocyte damage in metabolic liver disease. These findings led us to hypothesize that EFHD1 ablation protects hepatocytes in metabolic liver disease by preventing excessive mitochondrial fissioning, lowering mitochondrial dsRNA release and reducing hepatocyte damage by the ISR. We therefore propose that EFHD1 represents a novel therapeutic pathway to treat metabolic liver disease.