The effect of aging and acetyl‐L‐carnitine on the pyruvate transport andoxidation in rat heart mitochondria

Abstract

The effect of aging and acute treatment with acetyl-Lcarnitine on the pyruvate transport and oxidation in rat heart mitochondria was studied. The activity of the pyruvate carrier as well as the rates of pyruvate-supported respiration were both depressed (around 40%) in heart mitochondria from aged rats, the major decrease occurring during the second year of life. Administration of acetyI-L-carnitine to aged rats almost completely restored the rates of these metabolic functions to the level of young control rats. This effect of acetyl-L-carnitine was not due to changes in the content of pyruvate carrier molecules. The heart mitochondrial content of cardiolipin, a key phospholipid necessary for mitochondrial substrate transport, was markedly reduced (approximately 40%) in aged rats. Treatment of aged rats with acetyl-L-carnitine reversed the age-associated decline in cardiolipin content. As the changes in cardiolipin content were correlated with changes in rates of pyruvate transport and oxidation, it is suggested that acetyl-Lcarnitine reverses the age-related decrement in the mitochondrial pyruvate metabolism by restoring the normal cardiolipin content.

Acetyl-l-carnitine supplementation reverses the age-related decline in carnitine palmitoyltransferase 1 (CPT1) activity in interfibrillar mitochondria without changing the l-carnitine content in the rat heart

“…We and others have previously found that supplementation of old rats with ALCAR remediates the age-related decay in mitochondrial bioenergetics in liver (Hagen et al, 1998a, 1998b), heart (Paradies et al, 1994, 1999), muscle (Pesce et al, 2010) and brain (Liu et al, 2002). ALCAR has been postulated to mediate this improvement in a straightforward manner, namely, by replenishing L-carnitine levels which otherwise decline with age (Costell and Grisolia, 1993; Costell et al, 1989; Maccari et al, 1990; Tanaka et al, 2004).…”

“…If carnitine levels indeed contribute to lower CPT1 activity, then it is equally possible that general CPT1-mediated fatty acid oxidation can be remediated by increasing myocardial L-carnitine content. In this regard, cardiac mitochondrial bioenergetics in aged rats has been improved following dietary supplementation with the L-carnitine analogue, acetyl-L-carnitine (ALCAR) (Hagen et al, 2002; Paradies et al, 1994, 1995, 1999). …”

Mitochondrial pyruvate transport: a historical perspective and future research directions

“…In addition, Paradies and Ruggiero [116,117] suggested that hyperthyroidism increased rat heart MPC activity [116], whereas hypothyroid rats displayed decreased heart MPC activity [117]. These authors also observed age-related decreases in heart MPC activity in rats [118,119]. Last, in working guinea-pig hearts, it was suggested that MPC flux did not play acontrolling role in the rate of pyruvate oxidation because PDH activity was determined to be slower than the rate of pyruvate import [120].…”

Mitochondrial dysfunction in cardiac aging

“…This was observed alongside other improved parameters of mitochondrial ageing in the brain and suggests that preservation of intact cardiolipin is an avenue of abrogating age-related declines in mitochondrial function. Similarly, Paradies and colleagues have reported that acyl-carnitine supplementation in aged rats restored CL levels to that of young controls, and that some CL-dependent processes were improved [68, 75]. …”