Acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1) is a polyglycerophospholipid acyltransferase of the endoplasmic reticulum which is primarily known for catalyzing the acylation of monolysocardiolipin back into cardiolipin, although it does catalyze the acylation of other polyglycerophospholipids.[1]
ALCAT1 is widely distributed throughout the body, with the highest concentrations being in the heart and liver.[2]
Mechanism
ALCAT1 shares similar mechanism with other
acyltransferases that facilitates biosynthesis of esters from acyl-CoA and alcohol. In the first step, the free hydroxyl group on monolysocardiolipin is deprotonated to make a good nucleophilic attacker.[3]
Proposed CL remodeling pathways in aging. Aging causes oxidative stress, leading to the production of ROS. CL oxidation by ROS triggers the remodeling of its fatty acyl chains, which begins with hydrolysis of oxidized CL by cPLA2, followed by re-acylation of MLCL by either Tafazzin (TAZ), MLCLAT, or ALCAT1. Activity of TAZ and MLCLAT leads to mitochondrial recovery. ALCAT1 catalyzes remodeling of CL with MLCL and non-linoleic acyl-CoAs like DHA-CoA (C22:6) as substrates, leading to CL peroxidation by ROS and mitochondrial dysfunction.[6]
While competing against
mitochondrial dysfunction leads to more oxidative stress and reactive oxygen species (ROS), and consequently faster depletion of physiological cardiolipin due to oxidation. Moreover, the activity of ALCAT1 is up-regulated by oxidative stress, which closes the loop of a vicious cycle that is implicated in the pathogenesis of various age-related diseases.[6][8]
In animal studies, knockout of ALCAT1 improved cardiac function and inhibited the injury of the heart and kidney in mice with
Accumulating evidence suggests that over-expression of ALCAT1 is involved in pathological cardiolipin remodeling and mitochondrial bioenergetics. Up-regulated expression of ALCAT1 can increase the fraction of
coronary heart disease, and Parkinson's disease.[10] Therefore, ALCAT1 is suggested as a novel therapeutic target for the treatment of these diseases.[11]
ALCAT1 controls mitochondrial cause for age-related diseases in response to oxidative stress. ALCAT1 expression is up-regulated by ROS from oxidative stress associated with age-related diseases. Cardiolipin remodeling with poly-unsaturated fatty acids by ALCAT1 causes cardiolipin peroxidation, leading to a vicious cycle of ROS production, cardiolipins peroxidation, and mitochondrial dysfunction, which promotes the development of age-related metabolic disease.[6]
