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Solving the Mitochondrial Mystery
Products of Putative Pathway for de novo Fatty Acid Synthesis in Mammalian Mitochondria Identified by CHORI Researchers

For over 30 years, controversy has surrounded the existence, location and products of a mitochondrial pathway for de novo fatty acid synthesis in animals. Now, however, scientists Andrzej Witkowski, PhD and Stuart Smith, PhD, DSc, in CHORI's Center for the Prevention of Obesity, Cardiovascular Disease & Diabetes have demonstrated unequivocally the presence of the enzymes required for this pathway in the soluble matrix compartment of the mitochondria and have identified, for the first time, the nature of the fatty acid products.

Animal cells contain enzymes in the soluble cytoplasm that make fatty acids de novo and also contain membrane-associated enzymes that are able to elongate preexisting fatty acids. Many of the conflicting reports in the earlier literature regarding the mitochondrial pathway probably resulted from the use of mitochondria and sub-mitochondrial fractions contaminated with enzymes from these other sources. Dr. Smith and colleagues were determined not to make the same mistakes.

"We took great pains to make sure we had purified mitochondria," explains Dr. Smith. "We used marker enzymes to characterize our mitochondrial and submitochondrial preparations and verified the absence of enzymes that could have originated from other parts of the cell. We got a very clear picture as a result."

That picture revealed several novel findings, to say the least. First, it confirmed that a mitochondrial pathway does indeed exist and that it is located in the mitochondrial soluble matrix. Second, although the system is capable of producing fatty acids containing as many as 14 carbon atoms, the major product is an 8-carbon acyl chain. Third, the newly synthesized 8-carbon acyl chain is translocated to the lipoylation site on an acceptor protein, thus becoming the substrate for the production of lipoyl moieties.

Several mitochondrial enzymes that play essential roles in energy metabolism employ covalently-attached lipoyl moieties as integral components of their catalytic processes. Recent knockout mice studies have revealed that the inability to synthesize lipoyl moieties in utero is lethal to mouse embryos.

"The amazing thing was that mice didn't survive gestation and the mice couldn't be rescued by adding lipoic acid to the maternal diet, either," Dr. Smith says. "Putting all this together suggests that this pathway we've confirmed, which produces the fatty acid precursor for the biosynthesis of lipoyl moieties, may be critical for mammalian development."

Dr. Smith speculates that one of the reasons animals have retained a mitochondrial system for fatty acid synthesis may be to ensure that an adequate supply of lipoyl moieties is always available to service the enzymes that are essential to mitochondrial function. The next step is to determine how important this pathway is in animals at different stages of development.

"Does the pathway function well throughout life?" Dr. Smith asks. "Does it peter out as we get older? Can dietary lipoic acid provide the essential lipoyl moieties at certain stages of development?"

As part of their effort to answer these questions, Dr. Smith and his colleagues are working on developing a knockout mouse model that is defective in the mitochondrial fatty acid biosynthetic pathway. This is a potentially critical step in understanding human disease, as in recent years, there has been an increasing suspicion that many diseases of unknown etiology, such as Friedreich's ataxia, Parkinson's and other degenerative conditions, are the result of defective mitochondrial function.

Surprisingly however, of the approximately 1500 proteins present in mitochondria, less than half have been well characterized. Studies such as the one ongoing in Dr. Smith's lab may eventually identify the proteins responsible for these 'mitochondrial diseases.'

"If we're successful in generating our mouse strain, we'll be able to fully evaluate the importance of the pathway to mitochondrial function," says Dr. Smith.


Monday, May 16, 2011 11:33 PM

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