Abstract Body: Magnesium (Mg²⁺) is an abundant intracellular divalent cation and is an important co-factor. Like calcium, Mg²⁺ is also compartmentalized to mitochondria. Mrs2 is the only known molecular machinery associated with mitochondrial Mg²⁺ influx. Although we know that Mg²⁺ plays a crucial role in cellular homeostasis, our understanding of how mMg²⁺ homeostasis alters the metabolic state of the cell remains incomplete. To begin elucidating the importance of mMg²⁺, we made a liver-specific Mrs2 knockout mouse model (Mrs2^Dhep) using the Cre-loxP system. Since liver is the central hub of lipid metabolism, we hypothesized that loss of mitochondrial Mg²⁺ could alter hepatic lipid homeostasis. Enigmatically we observed increased hepatic lipid accumulation, in spite of increased PPARa activation and Fatty acid oxidation (FAO). In our previous work we showed in Mrs2^Dhep the FAO-derived acetyl CoA to be channeled to de novo lipogenesis (DNL) via cataplerosis, instead of ketogenesis. Further, our results show markedly blunted ketonemia in Mrs2^Dhep revealing a state of ketogenic insufficiency. In the presence of increased ketone bodies (KB), normal hearts preferentially use both KB and FAO while glucose metabolism tend to be reduced. During the progression of heart failure (HF), the failing heart depends on alternate ATP generating substrates like KB as there is a metabolic deficit in both FAO and glucose metabolism. Because we saw a decrease in the KB, we hypothesize that hepatic ketogenic insufficiency will lead to cardiac hypertrophy and heart failure in pressure overload model due to energy insufficiency. Interestingly we found the heart weight and the heart to body weight ratio, left ventricular (LV) wall thickness, expression of genes linked to cardiac hypertrophy to be increased in Mrs2^Dhep compared to control. We also observed an adverse structural remodeling of LV and LV dysfunction. Masson’s trichrome staining showed increased collagen deposition and fibrosis in the Mrs2^Dhep mice when compared to the control. Our results show altered hepatic mitochondrial Mg²⁺ homeostasis to have profound direct effect on hepatic lipid metabolism and indirect inter-organ effect on the heart following pressure overload.