Abstract
A mouse model with compromised mitochondrial fatty acid synthesis has been engineered in order to assess the role of this pathway in mitochondrial function and overall health. Reduction in the expression of mitochondrial malonyl CoA-acyl carrier protein transacylase, a key enzyme in the pathway encoded by the nuclear Mcat gene, was achieved to varying extents in all examined tissues employing tamoxifen-inducible Cre-lox technology. Although affected mice consumed more food than control animals, they failed to gain weight, were less physically active, suffered from loss of white adipose tissue, reduced muscle strength, kyphosis, alopecia, hypothermia and shortened lifespan. The Mcat-deficient phenotype is attributed primarily to reduced synthesis, in several tissues, of the octanoyl precursors required for the posttranslational lipoylation of pyruvate and α-ketoglutarate dehydrogenase complexes, resulting in diminished capacity of the citric acid cycle and disruption of energy metabolism. The presence of an alternative lipoylation pathway that utilizes exogenous free lipoate appears restricted to liver and alone is insufficient for preservation of normal energy metabolism. Thus, de novo synthesis of precursors for the protein lipoylation pathway plays a vital role in maintenance of mitochondrial function and overall vigor.
Highlights
According to the United Mitochondrial Disease Foundation, each year in the United States, as many as 4,000 children are born who will develop a mitochondrial disease by age 10
In vitro studies [9,10] have revealed that the major product of the mitochondrial pathway is an octanoyl moiety that can be utilized as a precursor for the formation of lipoyl moieties that are utilized for the posttranslation modification of key mitochondrial proteins that constitute the lipoamide subproteome: the E2 subunits of the pyruvate (PDC), a-ketoglutarate (KDC) and branched-chain aketoacid (BCDC) dehydrogenase complexes and the H-protein component of the glycine cleavage system (GCS)
Mcat catalyzes the transfer of malonyl moieties from CoA to the phosphopantetheinyl moiety of the acyl carrier protein (ACP) that is responsible for shuttling reaction intermediates through the catalytic centers of the enzymes participating in the pathway [3]
Summary
According to the United Mitochondrial Disease Foundation, each year in the United States, as many as 4,000 children are born who will develop a mitochondrial disease by age 10. Recently has it become clear that human mitochondria contain their own unique system for synthesizing fatty acids de novo that is encoded by nuclear genes [3,4,5,6,7,8]. These genes encode a suite of discrete individual proteins, termed type II fatty acid synthase, that is quite distinct from the megasynthase complex responsible for de novo fatty acid synthesis in the cytosolic compartment, the type I fatty acid synthase, in which the individual enzymes are covalently linked. The target for knockout was the nuclear gene Mcat that encodes the mitochondrial malonyl CoA-acyl carrier protein (ACP) transacylase. The structure and mechanism of action of Mcat has been elucidated [13]
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