In vivo assessment of hepatic mitochondria

Objectives: Mitochondrial dysfunction has been closely related to many pathologic processes, such as cellular apoptosis. Alterations in mitochondrial membrane potential (ΔΨ_m) are associated with mitochondrial dysfunction. The fluorine-18 labeled phosphonium compound ¹⁸F-triphenylphosphonium (¹⁸F-TPP) was used to measure the tissue membrane potential (ΔΨ_T), a proxy of ΔΨ_m, to quantitatively assess liver mitochondrial status.

Methods: Conceptually, liver tissue can be partitioned into two components: extracellular space (ECS), and intracellular space. Concentrations in cells are further partitioned into cytosolic and mitochondrial (f_mito) fractions. Five 120 minute dynamic scans were performed in domestic swine using PET/CT or PET/MR. The volume of distribution, V_T, of ¹⁸F-TPP⁺ of liver tissue was calculated using the Logan transformation. ECS was quantified using MR T1-mapping.

Results: We show that the volume of distribution of ¹⁸F-TPP⁺ can be expressed in terms of concentration ratios of the ECS, cytosol and mitochondria relative to the plasma. The Nernst equation relates the equilibrium concentrations of TPP⁺ on both sides of a permeable membrane to the membrane’s electric potential. V_T is linearly proportional to the product of volume fractions (1-f_ECS)×f_mito and an exponential function of the electrical potential across the cell and mitochondrial membranes. We derived a novel equation expressing V_T in terms of ΔΨ_T and ECS fraction. ECS fraction was measured to be 41%. In all 5 animals, there was small variation of ΔΨ_T ranging between -183 mV and -158 mV and with an average of -170.4±4.6 mV (mean±SEM).

Conclusion: We demonstrated for the first time the feasibility of noninvasive, in vivo, quantitative assessment of liver ΔΨ_T. In our model, the tissue-to-plasma ratio at equilibrium, V_T, is sensitive to two independent variables; the tissue fraction of the ECS and ΔΨ_T. In vivo quantification of the mitochondrial function could provide new diagnostic and prognostic information in liver diseases as well as allow therapy monitoring. Further investigations are required to assess these potential roles. Research Support: This work was supported in part by NIH grant: R01HL110241