Mitochondrial Fatty Acid Synthesis Type II: More than Just Fatty Acids

Eukaryotes harbor a highly conserved mitochondrial pathway for fatty acid synthesis (FAS), which is completely independent of the eukaryotic cytosolic FAS apparatus. The activities of the mitochondrial FAS system are catalyzed by soluble enzymes, and the pathway thus resembles its prokaryotic counterparts. Except for octanoic acid, which is the direct precursor for lipoic acid synthesis, other end products and functions of the mitochondrial FAS pathway are still largely enigmatic. In addition to low cellular levels of lipoic acid, disruption of genes encoding mitochondrial FAS enzymes in yeast results in a respiratory-deficient phenotype and small rudimentary mitochondria. Recently, two distinct links between mitochondrial FAS and RNA processing have been discovered in vertebrates and yeast, respectively. In vertebrates, the mitochondrial 3-hydroxyacyl-acyl carrier protein dehydratase and the RPP14 subunit of RNase P are encoded by the same bicistronic transcript in an evolutionarily conserved arrangement that is unusual for eukaryotes. In yeast, defects in mitochondrial FAS result in inefficient RNase P cleavage in the organelle. The intersection of mitochondrial FAS and RNA metabolism in both systems provides a novel mechanism for the coordination of intermediary metabolism in eukaryotic cells. Eukaryotes harbor a highly conserved mitochondrial pathway for fatty acid synthesis (FAS), which is completely independent of the eukaryotic cytosolic FAS apparatus. The activities of the mitochondrial FAS system are catalyzed by soluble enzymes, and the pathway thus resembles its prokaryotic counterparts. Except for octanoic acid, which is the direct precursor for lipoic acid synthesis, other end products and functions of the mitochondrial FAS pathway are still largely enigmatic. In addition to low cellular levels of lipoic acid, disruption of genes encoding mitochondrial FAS enzymes in yeast results in a respiratory-deficient phenotype and small rudimentary mitochondria. Recently, two distinct links between mitochondrial FAS and RNA processing have been discovered in vertebrates and yeast, respectively. In vertebrates, the mitochondrial 3-hydroxyacyl-acyl carrier protein dehydratase and the RPP14 subunit of RNase P are encoded by the same bicistronic transcript in an evolutionarily conserved arrangement that is unusual for eukaryotes. In yeast, defects in mitochondrial FAS result in inefficient RNase P cleavage in the organelle. The intersection of mitochondrial FAS and RNA metabolism in both systems provides a novel mechanism for the coordination of intermediary metabolism in eukaryotic cells. Mitochondrial research has been enjoying a renaissance during the last two decades because of major discoveries of previously unknown or overlooked processes such as mitochondrial fusion and fission, mechanisms and regulation of transcription and translation, iron-sulfur cluster biogenesis, structure and assembly of respiratory chain complexes, mitochondria-to-nucleus “retrograde” signaling, mechanisms of mitochondrial inheritance, programmed cell death, and the role of mitochondria in human disease. This review focuses on the process of fatty acid biosynthesis discovered relatively recently in mitochondria.The de novo synthesis of fatty acids in eukaryotes can take place in at least two subcellular compartments: in the cytoplasm (FAS 2The abbreviations used are: FAS, fatty acid synthesis; ACP, acyl carrier protein; PDH, pyruvate dehydrogenase. and in mitochondria (FAS synthesis has its in and is in has the FAS pathway been in the pathway provides of the cellular fatty respiratory in yeast is on the of mitochondria to fatty in eukaryotic encoding a small of of the respiratory chain and The genes are in or two in to in and or as such as in in processing is for the of mitochondrial because are between the in the precursor RNA and are of the RNase P is for the at the of the a distinct the have that fatty acid biosynthesis in mitochondria is to RNase P in vertebrates and assembly in intersection of two provides a for In are on or in in the are is that the intersection of the mitochondrial FAS pathway RNA processing has been as a to mitochondrial to the of the The of the intersection in yeast and vertebrates are The mitochondrial FAS pathway in yeast the or of mitochondrial RNase which the of mitochondrial precursor In and in other vertebrates as a bicistronic both the RPP14 subunit of RNase P and dehydratase in the FAS pathway FAS and cytosolic FAS pathway of in or two of in the mitochondrial pathway independent that in FAS The in the mitochondrial pathway acid to the of an and that the protein is in de novo synthesis of fatty acids in mitochondria eukaryotes to a mitochondrial of The of mitochondrial as a of the mitochondrial respiratory that mitochondria a soluble of the of mitochondrial ACP, the mitochondrial FAS pathway has been in This mitochondrial by the and the of enzymes for the synthesis of fatty acids in mitochondria. The yeast and are to prokaryotic the yeast has been to a mitochondrial to cytosolic The yeast that the two of the fatty acid and have to prokaryotic FAS in the yeast a in which the on a for in yeast to the of mitochondrial in and its in In to an of for a of that the of the protein to the mitochondrial and to the of yeast on a the of the which is completely respiratory-deficient at yeast in the mitochondrial FAS pathway mitochondrial at of the are a of mitochondrial and have low levels of lipoic In to the small mitochondria in of or results in of the mitochondrial to the yeast human FAS and and have been to the yeast In the that have been the genes in a of and the of fatty acids by the mitochondrial FAS pathway in cellular metabolism have been In is for the that the pathway is the of the octanoic acid precursor for the of the lipoic acid for PDH, and cleavage system a precursor to lipoic acid to the protein acid of the cleavage system mitochondrial soluble and acid is as a for and mitochondrial enzymes for the of the acid to have been a encoding a mitochondrial lipoic acid in a that of the lipoic acid in and by the of lipoic acid processes that lipoic acid in in addition to octanoic acid, is that the FAS pathway fatty In enzymes of the mitochondrial FAS pathway and to chain The the to fatty acid the recently structure of human a to acyl to in chain of that the mitochondrial FAS pathway fatty acids octanoic the human the of and as and the and of the for lipoic acid and have the acyl mitochondria that the fatty acids by the mitochondrial FAS pathway in are and acids The mitochondrial FAS pathway acid fatty acids end disruption of the mitochondrial FAS pathway by the of small RNA in cellular of the of yeast mitochondrial such as of and mitochondrial of or by the or of octanoic acid and a for fatty acids by the mitochondrial FAS pathway or addition to lipoic acid, in the mitochondrial a of of as acyl and as are in and to the of of has been in the of the in of mitochondria the of other chain acyl on in and to for in an of a role for mitochondrial in mitochondrial RNA that mitochondrial processing in in a that a in which lipoic acid This two octanoic acid to lipoic acid Mitochondrial processing RNase a that processes the of In the assembly of RNase P processing of a mitochondrial precursor RNA the RNA subunit of RNase P and in processing is the RNase P cleavage at the of the which RNA for and RNA the protein to the in for in mitochondrial RNA processing on genes encoding previously enzymes in the and of precursor a in the which the dehydratase in the mitochondrial FAS in processing of the precursor at the RNase P cleavage which the precursor RNA and links the mitochondrial FAS pathway in and The that an of fatty acid or lipoic acid synthesis or a the of RNase P processing of the precursor of other that by acid or of have been for fatty a FAS RNA of mitochondrial that have two independent functions have been the is for the of in mitochondrial precursor of the to and to In the mitochondrial RNA has a that is for protein synthesis is a the FAS enzymes and that in RNA of the precursor RNA the result of a in protein in RNA processing to of a of the mitochondrial FAS is the FAS pathway to processing the or of RNase In yeast, a of the mitochondrial FAS pathway is for of RNA and assembly of the RNase P or of RNase P that the protein of RNase P a lipoic have that is the a fatty acid or lipoic acid the RNase P or the or protein fatty acid RNase P assembly or that a mitochondrial FAS pathway a direct role in the of RNase P is by the that are in the of are for yeast and vertebrates, the the The in both at a mechanism for the regulation of mitochondrial in to cellular between a Mitochondrial FAS and an RNase P in mitochondrial FAS such as and on to and yeast human of or prokaryotic by encoding the human dehydratase by a in which the respiratory-deficient yeast human and and for to on a The of human the of a highly mitochondrial in which the of the human In the recently dehydratase is to human the in synthesis the or the that the the yeast human RPP14 which subunit of the mitochondrial RNase P of the an encoding mitochondrial The to for the yeast The bicistronic two and is in and human mitochondrial of unusual bicistronic arrangement in that the structure has been for eukaryotic are because is by the small which the the in of the of the dehydratase is of the RPP14 is a for of the mechanism of for the the that the has been that arrangement is regulation and is in the coordination of mitochondrial that a in yeast to mitochondrial in to pyruvate in FAS octanoic acid, which is the for lipoic acid acid is to the subunit of and is for the of pyruvate to which the FAS the pyruvate is for the FAS in levels of lipoic acid and in the yeast mitochondrial RNase P in which processing of the RNase P RNA the of the RNase P that two are disruption of the FAS pathway results in levels of precursor RNA and other mitochondrial have a direct on the synthesis of encoded of the respiratory chain and of mitochondrial FAS the that the pathway is an of the the that pathway a role in cellular metabolism is by the that of of the genes encoding mitochondrial FAS in yeast results in mitochondrial The for the respiratory of is a of cellular lipoic acid, which to of acid the between the of lipoic acid and inefficient mitochondrial RNA processing in yeast has been and the of a major for mitochondrial processing to mitochondrial RNase P the of mitochondrial protein synthesis and the of respiratory the at the of a of the FAS pathway the of the RNA and processing in yeast to a of mitochondria mitochondrial metabolism between the mitochondrial FAS pathway and RNA processing is in the of a subunit of RNase is the transcript is This unusual bicistronic transcript to an for the of mechanisms of a in a the of mitochondrial FAS in has is which are for the of other of the mitochondrial FAS pathway are in the mitochondrial the the mitochondrial the to the or in the mitochondrial is in that human mitochondrial has been and of the human of yeast has the of the on the of in the mitochondrial that the of the mitochondrial FAS pathway can acyl to a chain in This result is in the mitochondrial FAS enzymes the of the chain acyl a for an of chain is a of of mitochondria the of mitochondria to in yeast a mitochondrial FAS pathway is is a direct to of fatty acids or a to a mitochondrial to fatty acids and to Mitochondrial research has been enjoying a renaissance during the last two decades because of major discoveries of previously unknown or overlooked processes such as mitochondrial fusion and fission, mechanisms and regulation of transcription and translation, iron-sulfur cluster biogenesis, structure and assembly of respiratory chain complexes, mitochondria-to-nucleus “retrograde” signaling, mechanisms of mitochondrial inheritance, programmed cell death, and the role of mitochondria in human disease. This review focuses on the process of fatty acid biosynthesis discovered relatively recently in mitochondria. The de novo synthesis of fatty acids in eukaryotes can take place in at least two subcellular compartments: in the cytoplasm (FAS 2The abbreviations used are: FAS, fatty acid synthesis; ACP, acyl carrier protein; PDH, pyruvate dehydrogenase. and in mitochondria (FAS synthesis has its in and is in has the FAS pathway been in the pathway provides of the cellular fatty respiratory in yeast is on the of mitochondria to fatty in eukaryotic encoding a small of of the respiratory chain and The genes are in or two in to in and or as such as in in processing is for the of mitochondrial because are between the in the precursor RNA and are of the RNase P is for the at the of the a distinct the have that fatty acid biosynthesis in mitochondria is to RNase P in vertebrates and assembly in intersection of two provides a for In are on or in in the are is that the intersection of the mitochondrial FAS pathway RNA processing has been as a to mitochondrial to the of the The of the intersection in yeast and vertebrates are The mitochondrial FAS pathway in yeast the or of mitochondrial RNase which the of mitochondrial precursor In and in other vertebrates as a bicistronic both the RPP14 subunit of RNase P and dehydratase in the FAS pathway Mitochondrial FAS and cytosolic FAS pathway of in or two of in the mitochondrial pathway independent that in FAS The in the mitochondrial pathway acid to the of an and that the protein is in de novo synthesis of fatty acids in mitochondria eukaryotes to a mitochondrial of The of mitochondrial as a of the mitochondrial respiratory that mitochondria a soluble of the of mitochondrial ACP, the mitochondrial FAS pathway has been in This mitochondrial by the and the of enzymes for the synthesis of fatty acids in mitochondria. The yeast and are to prokaryotic the yeast has been to a mitochondrial to cytosolic The yeast that the two of the fatty acid and have to prokaryotic FAS in the yeast a in which the on a for in yeast to the of mitochondrial in and its in In to an of for a of that the of the protein to the mitochondrial and to the of yeast on a the of the which is completely respiratory-deficient at yeast in the mitochondrial FAS pathway mitochondrial at of the are a of mitochondrial and have low levels of lipoic In to the small mitochondria in of or results in of the mitochondrial to the yeast human FAS and and have been to the yeast In the that have been the genes in a of The cytosolic FAS pathway of in or two of in the mitochondrial pathway independent that in FAS The in the mitochondrial pathway acid to the of an and that the protein is in de novo synthesis of fatty acids in mitochondria eukaryotes to a mitochondrial of The of mitochondrial as a of the mitochondrial respiratory that mitochondria a soluble of the of mitochondrial ACP, the mitochondrial FAS pathway has been in This mitochondrial by the and the of enzymes for the synthesis of fatty acids in mitochondria. The yeast and are to prokaryotic the yeast has been to a mitochondrial to cytosolic The yeast that the two of the fatty acid and have to prokaryotic FAS in the yeast a in which the on a for in yeast to the of mitochondrial in and its in In to an of for a of that the of the protein to the mitochondrial and to the of yeast on a the of the which is completely respiratory-deficient at yeast in the mitochondrial FAS pathway mitochondrial at of the are a of mitochondrial and have low levels of lipoic In to the small mitochondria in of or results in of the mitochondrial to the yeast human FAS and and have been to the yeast In the that have been the genes in a of and the of fatty acids by the mitochondrial FAS pathway in cellular metabolism have been In is for the that the pathway is the of the octanoic acid precursor for the of the lipoic acid for PDH, and cleavage system a precursor to lipoic acid to the protein acid of the cleavage system mitochondrial soluble and acid is as a for and mitochondrial enzymes for the of the acid to have been a encoding a mitochondrial lipoic acid in a that of the lipoic acid in and by the of lipoic acid processes that lipoic acid in in addition to octanoic acid, is that the FAS pathway fatty In enzymes of the mitochondrial FAS pathway and to chain The the to fatty acid the recently structure of human a to acyl to in chain of that the mitochondrial FAS pathway fatty acids octanoic the human the of and as and the and of the for lipoic acid and have the acyl mitochondria that the fatty acids by the mitochondrial FAS pathway in are and acids The mitochondrial FAS pathway acid fatty acids end disruption of the mitochondrial FAS pathway by the of small RNA in cellular of the of yeast mitochondrial such as of and mitochondrial of or by the or of octanoic acid and a for fatty acids by the mitochondrial FAS pathway or addition to lipoic acid, in the mitochondrial a of of as acyl and as are in and to the of of has been in the of the in of mitochondria the of other chain acyl on in and to the of fatty acids by the mitochondrial FAS pathway in cellular metabolism have been In is for the that the pathway is the of the octanoic acid precursor for the of the lipoic acid for PDH, and cleavage system a precursor to lipoic acid to the protein acid of the cleavage system mitochondrial soluble and acid is as a for and mitochondrial enzymes for the of the acid to have been a encoding a mitochondrial lipoic acid in a that of the lipoic acid in and by the of lipoic acid processes that lipoic acid in in mitochondria. In addition to octanoic acid, is that the FAS pathway fatty In enzymes of the mitochondrial FAS pathway and to chain The the to fatty acid the recently structure of human a to acyl to in chain of that the mitochondrial FAS pathway fatty acids octanoic the human the of and as and the and of the for lipoic acid and have the acyl mitochondria that the fatty acids by the mitochondrial FAS pathway in are and acids The mitochondrial FAS pathway acid fatty acids end disruption of the mitochondrial FAS pathway by the of small RNA in cellular of the of yeast mitochondrial such as of and mitochondrial of or by the or of octanoic acid and a for fatty acids by the mitochondrial FAS pathway or In addition to lipoic acid, in the mitochondrial a of of as acyl and as are in and to the of of has been in the of the in of mitochondria the of other chain acyl on in and to for in an of a role for mitochondrial in mitochondrial RNA that mitochondrial processing in in a that a in which lipoic acid This two octanoic acid to lipoic acid Mitochondrial processing RNase a that processes the of In the assembly of RNase P processing of a mitochondrial precursor RNA the RNA subunit of RNase P and in processing is the RNase P cleavage at the of the which RNA for and RNA the protein to the in for in mitochondrial RNA processing on genes encoding previously enzymes in the and of precursor a in the which the dehydratase in the mitochondrial FAS in processing of the precursor at the RNase P cleavage which the precursor RNA a FAS RNA of mitochondrial that have two independent functions have been the is for the of in mitochondrial precursor of the to and to In the mitochondrial RNA has a that is for protein synthesis is a the FAS enzymes and that in RNA of the precursor RNA the result of a in protein in RNA processing to of a of the mitochondrial FAS is the FAS pathway to processing the or of RNase In yeast, a of the mitochondrial FAS pathway is for of RNA and assembly of the RNase P or of RNase P that the protein of RNase P a lipoic have that is the a fatty acid or lipoic acid the RNase P or the or protein fatty acid RNase P assembly or that a mitochondrial FAS pathway a direct role in the of RNase P is by the that are in the of are for yeast and vertebrates, the the The in both at a mechanism for the regulation of mitochondrial in to cellular an of a role for mitochondrial in mitochondrial RNA that mitochondrial processing in in a that a in which lipoic acid This two octanoic acid to lipoic acid Mitochondrial processing RNase a that processes the of In the assembly of RNase P processing of a mitochondrial precursor RNA the RNA subunit of RNase P and in processing is the RNase P cleavage at the of the which RNA for and RNA the protein to the in for in mitochondrial RNA processing on genes encoding previously enzymes in the and of precursor a in the which the dehydratase in the mitochondrial FAS in processing of the precursor at the RNase P cleavage which the precursor RNA a FAS RNA of mitochondrial that have two independent functions have been the is for the of in mitochondrial precursor of the to and to In the mitochondrial RNA has a that is for protein synthesis is a the FAS enzymes and that in RNA of the precursor RNA the result of a in protein in RNA processing to of a of the mitochondrial FAS is the FAS pathway to processing the or of RNase In yeast, a of the mitochondrial FAS pathway is for of RNA and assembly of the RNase P or of RNase P that the protein of RNase P a lipoic have that is the a fatty acid or lipoic acid the RNase P or the or protein fatty acid RNase P assembly or that a mitochondrial FAS pathway a direct role in the of RNase P is by the that are in the of are for yeast and vertebrates, the the The in both at a mechanism for the regulation of mitochondrial in to cellular between a Mitochondrial FAS and an RNase P in mitochondrial FAS such as and on to and yeast human of or prokaryotic by encoding the human dehydratase by a in which the respiratory-deficient yeast human and and for to on a The of human the of a highly mitochondrial in which the of the human In the recently dehydratase is to human the in synthesis the or the that the the yeast human RPP14 which subunit of the mitochondrial RNase P of the an encoding mitochondrial The to for the yeast The bicistronic two and is in and human mitochondrial of unusual bicistronic arrangement in that the structure has been for eukaryotic are because is by the small which the the in of the of the dehydratase is of the RPP14 is a for of the mechanism of for the the that the has been that arrangement is regulation and is in the coordination of mitochondrial mitochondrial FAS such as and on to and yeast human of or prokaryotic by encoding the human dehydratase by a in which the respiratory-deficient yeast human and and for to on a The of human the of a highly mitochondrial in which the of the human In the recently dehydratase is to human the in synthesis the or the that the the yeast human RPP14 which subunit of the mitochondrial RNase P of the an encoding mitochondrial The to for the yeast The bicistronic two and is in and human mitochondrial The of unusual bicistronic arrangement in that the structure has been for eukaryotic are because is by the small which the the in of the of the dehydratase is of the RPP14 is a for of the mechanism of for the the that the has been that arrangement is regulation and is in the coordination of mitochondrial that a in yeast to mitochondrial in to pyruvate in FAS octanoic acid, which is the for lipoic acid acid is to the subunit of and is for the of pyruvate to which the FAS the pyruvate is for the FAS in levels of lipoic acid and in the yeast mitochondrial RNase P in which processing of the RNase P RNA the of the RNase P that two are disruption of the FAS pathway results in levels of precursor RNA and other mitochondrial have a direct on the synthesis of encoded of the respiratory chain that a in yeast to mitochondrial in to pyruvate in FAS octanoic acid, which is the for lipoic acid acid is to the subunit of and is for the of pyruvate to which the FAS the pyruvate is for the FAS in levels of lipoic acid and in the yeast mitochondrial RNase P in which processing of the RNase P RNA the of the RNase P that two are disruption of the FAS pathway results in levels of precursor RNA and other mitochondrial have a direct on the synthesis of encoded of the respiratory chain and of mitochondrial FAS the that the pathway is an of the the that pathway a role in cellular metabolism is by the that of of the genes encoding mitochondrial FAS in yeast results in mitochondrial The for the respiratory of is a of cellular lipoic acid, which to of acid the between the of lipoic acid and inefficient mitochondrial RNA processing in yeast has been and the of a major for mitochondrial processing to mitochondrial RNase P the of mitochondrial protein synthesis and the of respiratory the at the of a of the FAS pathway the of the RNA and processing in yeast to a of mitochondria mitochondrial metabolism between the mitochondrial FAS pathway and RNA processing is in the of a subunit of RNase is the transcript is This unusual bicistronic transcript to an for the of mechanisms of a in a the of mitochondrial FAS in has is which are for the of other of the mitochondrial FAS pathway are in the mitochondrial the the mitochondrial the to the or in the mitochondrial is in that human mitochondrial has been and of the human of yeast has the of the on the of in the mitochondrial that the of the mitochondrial FAS pathway can acyl to a chain in This result is in the mitochondrial FAS enzymes the of the chain acyl a for an of chain is a of of mitochondria the of mitochondria to in yeast a mitochondrial FAS pathway is is a direct to of fatty acids or a to a mitochondrial to fatty acids and to The of mitochondrial FAS the that the pathway is an of the the that pathway a role in cellular metabolism is by the that of of the genes encoding mitochondrial FAS in yeast results in mitochondrial The for the respiratory of is a of cellular lipoic acid, which to of acid the between the of lipoic acid and inefficient mitochondrial RNA processing in yeast has been and the of a major for mitochondrial processing to mitochondrial RNase P the of mitochondrial protein synthesis and the of respiratory the at the of a of the FAS pathway the of the RNA and processing in yeast to a of mitochondria mitochondrial metabolism The between the mitochondrial FAS pathway and RNA processing is in the of a subunit of RNase is the transcript is This unusual bicistronic transcript to an for the of mechanisms of a in a the of mitochondrial FAS in has is which are for the of other of the mitochondrial FAS pathway are in the mitochondrial the the mitochondrial the to the or in the mitochondrial is in that human mitochondrial has been and of the human of yeast has the of the on the of in the mitochondrial that the of the mitochondrial FAS pathway can acyl to a chain in This result is in the mitochondrial FAS enzymes the of the chain acyl a for an of chain is a of of mitochondria the of mitochondria to in yeast a mitochondrial FAS pathway is is a direct to of fatty acids or a to a mitochondrial to fatty acids and to and and