Pyruvate inhibition of pyruvate dehydrogenase kinase

Abstract

Both prolonged starvation and hyperthyroidism evoke stable increases in cardiac pyruvate dehydrogenase kinase (PDHK) activity. Pyruvate inhibits PDHK in rat heart mitochondria with activation of PDHC. The sensitivity of PDHK to inhibition by pyruvate declines after prolonged starvation, in the present study, pyruvate concentrations giving 50% active complex (PDHa) in mitochondria from fed, control and fed, hyperthyroid rats were 0.3 and 0.8 mM, respectively, compared with 1.0 and 2.8 mM, respectively in mitochondria from 24-h-starved and 48-h-starved rats. The results demonstrate that altered pyruvate sensitivity is not of necessity linked with altered PDHK activity. PDHK activities in mitochondria prepared from cardiac myocytes from fed rats were increased after culture for 24 h with dibutyryl cyclic AMP (50 I.tM) plus noctanoate (1 mM), with a concomitant decline in sensitivity of PDHK to pyruvate inhibition, suggesting that changes in sensitivity of PDHK to pyruvate inhibition in vivo may be secondary to increased fatty acid supply and cyclic AMP concentrations.

Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation

“…Consistent with the characteristics of regulation of the recombinant PDK4 protein by dichloroacetate identified in vitro [1], enhanced skeletal muscle and cardiac PDK4 protein expression after prolonged starvation is associated with a rightward shift in the sensitivity curve for suppression of PDK activity by pyruvate and attenuation of the maximal response of PDK to suppression by pyruvate [15,49]. Thus relative insensitivity of PDK to suppression by pyruvate in heart and oxidative skeletal muscle after prolonged starvation [15,49] correlates with selectively enhanced PDK4 protein expression [9,40]. On the basis of these studies, we have developed the concept that in muscle PDK4 may be a 'lipid-status'-responsive PDK isoform, and that an increase in its expression relative to that of PDK2 may facilitate fatty acid oxidation by conserving pyruvate for oxaloacetate formation to allow entry of acetyl-CoA derived from fatty acid into the tricarboxylic acid cycle and regeneration of intramitochondrial CoA [16] (reviewed in [50]).…”

“…Recombinant PDK2 is the most sensitive (K i , 0.2 mM) to inhibition by the pyruvate analogue dichloroacetate, whereas recombinant PDK4 is relatively insensitive to suppression by dichloroacetate, but more responsive to an increased NADH/NAD + concentration ratio than recombinant PDK2 [1]. Consistent with the characteristics of regulation of the recombinant PDK4 protein by dichloroacetate identified in vitro [1], enhanced skeletal muscle and cardiac PDK4 protein expression after prolonged starvation is associated with a rightward shift in the sensitivity curve for suppression of PDK activity by pyruvate and attenuation of the maximal response of PDK to suppression by pyruvate [15,49]. Thus relative insensitivity of PDK to suppression by pyruvate in heart and oxidative skeletal muscle after prolonged starvation [15,49] correlates with selectively enhanced PDK4 protein expression [9,40].…”

Different mechanisms underlie the long‐term regulation of pyruvate dehydrogenase kinase (PDHK) by tri‐iodothyronine in heart and liver

“…PDHK activities were assayed at pH 7.0 in extracts of heart mitochondria by the rate of ATP‐dependent inactivation of fully activated PDHC and computed as apparent pseudo first order rate constants for ATP‐dependent PDHa inactivation [16]. Details of these methods are provided in [5, 9, 16].…”

“…Increasing mitochondrial [acetyl‐CoA]/[CoA] and [NADH]/[NAD + ] ratios activate PDHK, whereas increasing pyruvate concentrations suppress its activity [3]. It has been proposed previously that the long‐term increase in PDHK activity in liver observed in response to prolonged starvation is a consequence of an increase in PDHK specific activity rather than increased PDHK protein (reviewed in [4]; see also [5]). In experiments in tissue culture with hepatocytes and cardiac myocytes, fatty acids and cAMP have been shown to be possible mediators of the effects of starvation to increase PDH kinase activity [6–9].…”

Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart

“…The results indicate that control of the amount of PDK4 is important in long-term regulation of the activity of the pyruvate dehydrogenase complex in rat heart. independent of short-term effects of small molecule effectors [7][8][9][10][11][12][13][14][15][16]. Although considerable study of the purified complex has resulted in some understanding of short-term regulation, the molecular mechanisms responsible for long-term control have remained elusive.…”