The SLC25A47 locus controls gluconeogenesis and energy expenditure

Significance

Given the impenetrable nature of the mitochondrial inner-membrane, most of the known metabolite carrier proteins, including SLC25A family members, are ubiquitously expressed in mammalian tissues. One exception is SLC25A47, which is selectively expressed in the liver. The present study showed that depletion of SLC25A47 reduced mitochondrial pyruvate flux and hepatic gluconeogenesis under a fasted state, while activating energy expenditure. The present work offers a liver-specific target through which we can restrict hepatic gluconeogenesis, which is often in excess under hyperglycemic and diabetic conditions.

Abstract

Mitochondria provide essential metabolites and adenosine triphosphate (ATP) for the regulation of energy homeostasis. For instance, liver mitochondria are a vital source of gluconeogenic precursors under a fasted state. However, the regulatory mechanisms at the level of mitochondrial membrane transport are not fully understood. Here, we report that a liver-specific mitochondrial inner-membrane carrier SLC25A47 is required for hepatic gluconeogenesis and energy homeostasis. Genome-wide association studies found significant associations between  SLC25A47 and fasting glucose, HbA1c, and cholesterol levels in humans. In mice, we demonstrated that liver-specific depletion of SLC25A47 impaired hepatic gluconeogenesis selectively from lactate, while significantly enhancing whole-body energy expenditure and the hepatic expression of FGF21. These metabolic changes were not a consequence of general liver dysfunction because acute SLC25A47 depletion in adult mice was sufficient to enhance hepatic FGF21 production, pyruvate tolerance, and insulin tolerance independent of liver damage and mitochondrial dysfunction. Mechanistically, SLC25A47 depletion leads to impaired hepatic pyruvate flux and malate accumulation in the mitochondria, thereby restricting hepatic gluconeogenesis. Together, the present study identified a crucial node in the liver mitochondria that regulates fasting-induced gluconeogenesis and energy homeostasis.