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

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.