Glucagon regulation of oxidative phosphorylation requires an increase in matrix adenine nucleotide content through Ca2+ activation of the mitochondrial ATP-Mg/Pi carrier SCaMC-3.
It has been known for a long time that mitochondria isolated from hepatocytes treated with glucagon or Ca(2+)-mobilizing agents such as phenylephrine show an increase in their adenine nucleotide (AdN) content, respiratory activity, and calcium retention capacity (CRC). Here, we have studied the role of SCaMC-3/slc25a23, the mitochondrial ATP-Mg/Pi carrier present in adult mouse liver, in the control of mitochondrial AdN levels and respiration in response to Ca(2+) signals as a candidate target of glucagon actions. With the use of SCaMC-3 knock-out (KO) mice, we have found that the carrier is responsible for the accumulation of AdNs in liver mitochondria in a strictly Ca(2+)-dependent way with an S0.5 for Ca(2+) activation of 3.3 ± 0.9 μm. Accumulation of matrix AdNs allows a SCaMC-3-dependent increase in CRC. In addition, SCaMC-3-dependent accumulation of AdNs is required to acquire a fully active state 3 respiration in AdN-depleted liver mitochondria, although further accumulation of AdNs is not followed by increases in respiration. Moreover, glucagon addition to isolated hepatocytes increases oligomycin-sensitive oxygen consumption and maximal respiratory rates in cells derived from wild type, but not SCaMC-3-KO mice and glucagon administration in vivo results in an increase in AdN content, state 3 respiration and CRC in liver mitochondria in wild type but not in SCaMC-3-KO mice. These results show that SCaMC-3 is required for the increase in oxidative phosphorylation observed in liver mitochondria in response to glucagon and Ca(2+)-mobilizing agents, possibly by allowing a Ca(2+)-dependent accumulation of mitochondrial AdNs and matrix Ca(2+), events permissive for other glucagon actions.
Departmento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-CSIC; Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER) 28049 Madrid.
Ignacio
I
Amigo
Departmento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-CSIC; Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER) 28049 Madrid.
Javier
J
Traba
Departamento de Medicina Celular y Molecular, Centro de Investigaciones Biológicas (CIB), Consejo Superior de Investigaciones Científicas 28040 Madrid.
M Mar
MM
González-Barroso
Departmento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-CSIC; Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER) 28049 Madrid.
Carlos B
CB
Rueda
Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid 28040 Madrid.
Margarita
M
Fernández
Departamento de Medicina Celular y Molecular, Centro de Investigaciones Biológicas (CIB), Consejo Superior de Investigaciones Científicas 28040 Madrid.
Eduardo
E
Rial
Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid 28040 Madrid.
Aránzazu
A
Sánchez
Departmento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-CSIC; Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER) 28049 Madrid. Electronic address: jsatrustegui@cbm.uam.es.
Jorgina
J
Satrústegui
Área de Bioquímica, Centro Regional de Investigaciones Biomédicas, Facultad de Ciencias Ambientales y Bioquímica, Universidad de Castilla La Mancha (UCLM), Avda. Carlos III s/n, Toledo 45071, Spain. Electronic address: araceli.arco@uclm.es.
Araceli
A
Del Arco
D000227:Adenine Nucleotides / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D017920:Antiporters / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D005786:Gene Expression Regulation; D005934:Glucagon / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008954:Models, Biological; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption
C086357:ATP-Mg-Pi carrier proteins, mitochondria; D000227:Adenine Nucleotides; D017920:Antiporters; D024101:Mitochondrial Proteins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D005934:Glucagon; D005947:Glucose; D010100:Oxygen; D002118:Calcium