Stress response and energy metabolism as a function of aging

National Heart, Lung, And Blood Institute

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed nations. Mitochondrial dysfunction plays a central role in the pathogenesis of NAFLD, but the mechanisms underlying the dysfunction is poorly understood. Here, we show that Endonuclease G (EndoG), a nuclear-encoded mitochondrial endonuclease protects against fatty liver. Its expression is reduced in NAFLD liver in both mice and humans independent of whole-body obesity, and EndoG KO mice accumulate hepatic fat without developing whole-body obesity. Mitochondria-encoded RNAs are cleaved from a long polycistronic precursor RNA transcribed from each strand of the mitochondrial genome. EndoG increases intra-mitochondrial protein synthesis and mitochondrial respiration. Analyses of the oxygen consumption rate (OCR) at the individual mitochondrion level by fluorescent life-time microscopy (FLIM) shows that EndoG KO leads to the loss of high-OCR mitochondrial subpopulation. In conclusion, EndoG is an obesity-independent determinant of hepatic lipid accumulation and may be a potential target for the treatment of fatty liver.