Regulation of intracellular and mitochondrial sodium in health and disease

Abstract

The transmembrane sodium gradient is essential for both excitability of the cardiac cell and the regulation of the cytoplasmic concentrations of Ca and protons. In addition, movements of Na across the mitochondrial membrane affect matrix protons and calcium. In the first part of the review, we discuss the most important pathways responsible for sarcolemmal and mitochondrial sodium movements. The bulk of the review considers the changes of intracellular Na concentration ([Na(+)](i)) that occur in disease, specifically, ischemia, reperfusion, and heart failure. We review evidence implicating the increase of intracellular sodium to either increased influx of sodium (via either sodium channels or sodium/hydrogen exchange) or, alternatively, to decreased efflux on the Na/K pump. Although much has been learned about sodium regulation in the heart, there are still many unanswered questions, particularly concerning mitochondrial Na regulation.

Fig. 1

Schematic diagram of sarcolemmal and mitochondrial fluxes. On the sarcolemma the following transporters and channels are shown (clockwise): Na-K pump; Na-Ca exchange (NCX) working in Ca efflux (forward) mode; NCX working in Ca influx (reverse) mode; Na channel; Na-K exchange (NHE); Ca channel On the mitochondria the transporters and channels shown are (clockwise): Na-Ca exchange (NCE) in Ca entry mode; Na-H exchange; NCE in Ca efflux mode; Ca uniporter; pyruvate transporter; phosphate transporter; F₁F₀-ATPase; complex I–IV of the respiratory chain. The figure is in three parts. A. Control: [Na⁺]_i is about 8 mmol/L and pH_i about 7.2. [Ca²⁺]_i will vary between about 100 nmol/L in diastole and 1 μmol/L in systole. B. Ischemia. At the sarcolemma (clockwise), the following changes are indicated. [ATP]i is decreased affecting the Na-K pump. As shown by the arrows the reverse mode of NCX is increased. Na influx in increased particularly on the persistent Na channel. Na-H activity is increased. Anaerobic glycolysis produces lactic acid thereby acidifying the cell. There is also an increase of [Ca²⁺]_i to 3 μmol/L, a decrease of pH_i to 6.0 and an increase of [Na⁺]_i to 35–40 mM. At the mitochondria (clockwise) changes are. Increased Ca entry and Na efflux on NCE. Cessation of electron transport and proton efflux and net ATP synthesis by mitochondria. C. Heart Failure. Here the major sarcolemmal changes compared to control are: an increase in Na influx on the reverse mode of NCX; increase of NHE and increase of Na entry through Na channels. The increase of [Na⁺]_i to 15 mmol/L will result in more Na entry to mitochondria.

Fig. 1

Schematic diagram of sarcolemmal and mitochondrial fluxes. On the sarcolemma the following transporters and channels are shown (clockwise): Na-K pump; Na-Ca exchange (NCX) working in Ca efflux (forward) mode; NCX working in Ca influx (reverse) mode; Na channel; Na-K exchange (NHE); Ca channel On the mitochondria the transporters and channels shown are (clockwise): Na-Ca exchange (NCE) in Ca entry mode; Na-H exchange; NCE in Ca efflux mode; Ca uniporter; pyruvate transporter; phosphate transporter; F₁F₀-ATPase; complex I–IV of the respiratory chain. The figure is in three parts. A. Control: [Na⁺]_i is about 8 mmol/L and pH_i about 7.2. [Ca²⁺]_i will vary between about 100 nmol/L in diastole and 1 μmol/L in systole. B. Ischemia. At the sarcolemma (clockwise), the following changes are indicated. [ATP]i is decreased affecting the Na-K pump. As shown by the arrows the reverse mode of NCX is increased. Na influx in increased particularly on the persistent Na channel. Na-H activity is increased. Anaerobic glycolysis produces lactic acid thereby acidifying the cell. There is also an increase of [Ca²⁺]_i to 3 μmol/L, a decrease of pH_i to 6.0 and an increase of [Na⁺]_i to 35–40 mM. At the mitochondria (clockwise) changes are. Increased Ca entry and Na efflux on NCE. Cessation of electron transport and proton efflux and net ATP synthesis by mitochondria. C. Heart Failure. Here the major sarcolemmal changes compared to control are: an increase in Na influx on the reverse mode of NCX; increase of NHE and increase of Na entry through Na channels. The increase of [Na⁺]_i to 15 mmol/L will result in more Na entry to mitochondria.