Loss of Mitochondrial Pyruvate Carrier 2 in the Liver Leads to Defects in Gluconeogenesis and Compensation via Pyruvate-Alanine Cycling.
Pyruvate transport across the inner mitochondrial membrane is believed to be a prerequisite for gluconeogenesis in hepatocytes, which is important for the maintenance of normoglycemia during prolonged food deprivation but also contributes to hyperglycemia in diabetes. To determine the requirement for mitochondrial pyruvate import in gluconeogenesis, mice with liver-specific deletion of mitochondrial pyruvate carrier 2 (LS-Mpc2(-/-)) were generated. Loss of MPC2 impaired, but did not completely abolish, hepatocyte conversion of labeled pyruvate to TCA cycle intermediates and glucose. Unbiased metabolomic analyses of livers from fasted LS-Mpc2(-/-) mice suggested that alterations in amino acid metabolism, including pyruvate-alanine cycling, might compensate for the loss of MPC2. Indeed, inhibition of pyruvate-alanine transamination further reduced mitochondrial pyruvate metabolism and glucose production by LS-Mpc2(-/-) hepatocytes. These data demonstrate an important role for MPC2 in controlling hepatic gluconeogenesis and illuminate a compensatory mechanism for circumventing a block in mitochondrial pyruvate import.
Division of Geriatrics and Nutritional Sciences, Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Kyle S
KS
McCommis
Division of Geriatrics and Nutritional Sciences, Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Zhouji
Z
Chen
Advanced Imaging Research Center and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Xiaorong
X
Fu
Metabolic Solutions Development Company, Kalamazoo, MI 49007, USA.
William G
WG
McDonald
Metabolic Solutions Development Company, Kalamazoo, MI 49007, USA.
Jerry R
JR
Colca
Metabolic Solutions Development Company, Kalamazoo, MI 49007, USA.
Rolf F
RF
Kletzien
Advanced Imaging Research Center and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Shawn C
SC
Burgess
Division of Geriatrics and Nutritional Sciences, Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: bfinck@dom.wustl.edu.
Brian N
BN
Finck
D000409:Alanine / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002460:Cell Line; D002952:Citric Acid Cycle; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D005943:Gluconeogenesis; D006003:Glycogen / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006943:Hyperglycemia / Q000517:prevention & control; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000201:enzymology; D045664:Proprotein Convertase 1 / Q000235:genetics / Q000378:metabolism; D045706:Proprotein Convertase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism*
D001786:Blood Glucose; D019289:Pyruvic Acid; D006003:Glycogen; C473656:Pcsk1 protein, mouse; D045664:Proprotein Convertase 1; C473668:Pcsk2 protein, mouse; D045706:Proprotein Convertase 2; D000409:Alanine