Mic19 depletion impairs endoplasmic reticulum (ER)-mitochondrial contacts and mitochondrial lipid metabolism, leading to liver disease. Mic19, a key subunit of the MICOS complex, regulates ER-mitochondrial contacts through the EMC2-SLC25A46-Mic19 axis. Mic19 liver-specific knockout (LKO) reduces ER-mitochondrial contacts, disrupts mitochondrial lipid metabolism, and causes mitochondrial cristae disorganization and mitochondrial unfolded protein response (UPRmt), leading to nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Re-expression of Mic19 in Mic19 LKO hepatocytes blocks liver disease development. Mic19 overexpression suppresses MCD-induced fatty liver disease. The study reveals that the EMC2-SLC25A46-Mic19 axis regulates ER-mitochondrial contacts and is involved in mitochondrial lipid metabolism. Impairment of ER-mitochondrial contacts may be a mechanism associated with the development of NASH and liver fibrosis. Mic19 is involved in the regulation of ER-mitochondrial contacts and mitochondrial lipid metabolism. Mic19 deficiency causes mitochondrial phospholipid disorder, leading to mitochondrial structural abnormalities and stress. Mic19 LKO causes mitochondrial membrane disorganization and UPRmt in mouse liver. Mic19 LKO impairs liver fatty acid metabolism, leading to increased fatty acid and triglyceride levels in the liver. Mic19 LKO causes NASH and liver fibrosis in mice. Mic19 re-expression in Mic19 LKO mice restores liver lipid metabolism and blocks liver diseases. Mic19 overexpression suppresses MCD-induced fatty liver disease. The study highlights the role of Mic19 in maintaining ER-mitochondrial contacts and mitochondrial lipid metabolism, and its dysfunction is involved in the occurrence and development of liver diseases.Mic19 depletion impairs endoplasmic reticulum (ER)-mitochondrial contacts and mitochondrial lipid metabolism, leading to liver disease. Mic19, a key subunit of the MICOS complex, regulates ER-mitochondrial contacts through the EMC2-SLC25A46-Mic19 axis. Mic19 liver-specific knockout (LKO) reduces ER-mitochondrial contacts, disrupts mitochondrial lipid metabolism, and causes mitochondrial cristae disorganization and mitochondrial unfolded protein response (UPRmt), leading to nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Re-expression of Mic19 in Mic19 LKO hepatocytes blocks liver disease development. Mic19 overexpression suppresses MCD-induced fatty liver disease. The study reveals that the EMC2-SLC25A46-Mic19 axis regulates ER-mitochondrial contacts and is involved in mitochondrial lipid metabolism. Impairment of ER-mitochondrial contacts may be a mechanism associated with the development of NASH and liver fibrosis. Mic19 is involved in the regulation of ER-mitochondrial contacts and mitochondrial lipid metabolism. Mic19 deficiency causes mitochondrial phospholipid disorder, leading to mitochondrial structural abnormalities and stress. Mic19 LKO causes mitochondrial membrane disorganization and UPRmt in mouse liver. Mic19 LKO impairs liver fatty acid metabolism, leading to increased fatty acid and triglyceride levels in the liver. Mic19 LKO causes NASH and liver fibrosis in mice. Mic19 re-expression in Mic19 LKO mice restores liver lipid metabolism and blocks liver diseases. Mic19 overexpression suppresses MCD-induced fatty liver disease. The study highlights the role of Mic19 in maintaining ER-mitochondrial contacts and mitochondrial lipid metabolism, and its dysfunction is involved in the occurrence and development of liver diseases.