Faculty Collaboration Database

A biophysical model of the mitochondrial ATP-Mg/P(i) carrier. Biophys J 2012 Oct 03;103(7):1616-25

Date

10/16/2012

Pubmed ID

23062354

Pubmed Central ID

PMC3471468

DOI

10.1016/j.bpj.2012.08.050

Scopus ID

2-s2.0-84867025862 (requires institutional sign-in at Scopus site)   8 Citations

Abstract

Mitochondrial adenine nucleotide (AdN) content is regulated through the Ca(2+)-activated, electroneutral ATP-Mg/P(i) carrier (APC). The APC is a protein in the mitochondrial carrier super family that localizes to the inner mitochondrial membrane (IMM). It is known to modulate a number of processes that depend on mitochondrial AdN content, such as gluconeogenesis, protein synthesis, and citrulline synthesis. Despite this critical role, a kinetic model of the underlying mechanism has not been developed and validated. Here, a biophysical model of the APC is developed that is thermodynamically balanced and accurately reproduces a number of reported data sets from isolated rat liver and rat kidney mitochondria. The model is based on an ordered bi-bi mechanism for heteroexchange of ATP and P(i) and includes homoexchanges of ATP and P(i) to explain both the initial rate and time course data on ATP and P(i) transport via the APC. The model invokes seven kinetic parameters regarding the APC mechanism and three parameters related to matrix pH regulation by external P(i). These parameters are estimated based on 19 independent data curves; the estimated parameters are validated using six additional data curves. The model takes into account the effects of pH, Mg(2+), and Ca(2+) on ATP and P(i) transport via the APC, and supports the conclusion that the pH gradient across the IMM serves as the primary driving force for AdN uptake or efflux. Moreover, computer simulations demonstrate that extramatrix Ca(2+) modulates the turnover rate of the APC and not the binding affinity of ATP, as previously suggested.

Author List

Tewari SG, Dash RK, Beard DA, Bazil JN

Author

Ranjan K. Dash PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Animals
Biological Transport
Biophysical Phenomena
Hydrogen-Ion Concentration
Kidney
Kinetics
Liver
Mitochondria
Mitochondrial Membrane Transport Proteins
Models, Biological
Rats