Mitochondrial fatty acid synthesis, fatty acids and mitochondrial physiology

Kastaniotis, Alexander J.; Autio, Kaija J.; Kerätär, Juha M.; Monteuuis, Geoffray; Mäkelä, Anne; Nair, R.; Pietikäinen, Laura P.; Shvetsova, Antonina; Chen, Zhijun; Hiltunen, J. Kalervo

doi:10.1016/j.bbalip.2016.08.011

Cited by 125 publications

(84 citation statements)

References 122 publications

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“…P. infestans has three gene copies for this enzyme, one of which is predicted to encode a mitochondrial isoform (PITG_18025). It has been reported that many eukaryotes have a highly conserved, independent mitochondrial FAB pathway that is crucial for development (Hiltunen et al ., ; Kastaniotis et al ., ). Phytophthora spp.…”

Section: Resultsmentioning

confidence: 97%

Genome‐wide characterization of Phytophthora infestans metabolism: a systems biology approach

Rodenburg

Seidl

Ridder

et al. 2018

Molecular Plant Pathology

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SUMMARYGenome-scale metabolic models (GEMs) provide a functional view of the complex network of biochemical reactions in the living cell. Initially mainly applied to reconstruct the metabolism of model organisms, the availability of increasingly sophisticated reconstruction methods and more extensive biochemical databases now make it possible to reconstruct GEMs for less wellcharacterized organisms, and have the potential to unravel the metabolism in pathogen-host systems. Here, we present a GEM for the oomycete plant pathogen Phytophthora infestans as a first step towards an integrative model with its host. We predict the biochemical reactions in different cellular compartments and investigate the gene-protein-reaction associations in this model to obtain an impression of the biochemical capabilities of P. infestans. Furthermore, we generate life stage-specific models to place the transcriptomic changes of the genes encoding metabolic enzymes into a functional context. In sporangia and zoospores, there is an overall down-regulation, most strikingly reflected in the fatty acid biosynthesis pathway. To investigate the robustness of the GEM, we simulate gene deletions to predict which enzymes are essential for in vitro growth. This model is an essential first step towards an understanding of P. infestans and its interactions with plants as a system, which will help to formulate new hypotheses on infection mechanisms and disease prevention.

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Section: Resultsmentioning

confidence: 97%

Genome‐wide characterization of Phytophthora infestans metabolism: a systems biology approach

Rodenburg

Seidl

Ridder

et al. 2018

Molecular Plant Pathology

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“…Overall, fewer proteins are involved in synthesis than in bacteria: a single KS, for example, is responsible for all the condensation steps in the mitochondrion. The following description relates to mitochondrial fatty acid synthesis in humans and in Saccharomyces cerevisiae . Even though the transfer of malonyl moieties to the ACPs is catalyzed by specific malonyl‐CoA:ACP transacylases [Mct1 (yeast) or MCAT (human)], no mitochondrial acetyltransferase has been described yet, but acetyl‐ACP might be generated by transfer of acetylated phosphopantetheine from CoA to ACP through the action of the PPT .…”

Section: The Structure Of Type II Fassmentioning

confidence: 99%

Fatty Acid Biosynthesis: Chain‐Length Regulation and Control

et al. 2019

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De novo biosynthesis of fatty acids is an iterative process requiring strict regulation of the lengths of the produced fatty acids. In this review, we focus on the factors determining chain lengths in fatty acid biosynthesis. In a nutshell, the process of chain‐length regulation can be understood as the output of a chain‐elongating C−C bond forming reaction competing with a terminating fatty acid release function. At the end of each cycle in the iterative process, the synthesizing enzymes need to “decide” whether the growing chain is to be elongated through another cycle or released as the “mature” fatty acid. Recent research has shed light on the factors determining fatty acid chain length and has also achieved control over chain length for the production of the technologically interesting short‐chain (C4–C8) and medium‐chain (C10–C14) fatty acids.

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“…The pathways of CoA biosynthesis, mitochondrial fatty acid synthesis, and glycolysis/TCA cycle show interdependency and interconnectivity (Leonardi et al, 2005;Strauss, 2010;Beld et al, 2014;Kastaniotis et al, 2017; Fig 1), but a specific molecular etiology common to these four disorders has been lacking.…”

Section: Introductionmentioning

confidence: 99%

CoA‐dependent activation of mitochondrial acyl carrier protein links four neurodegenerative diseases

Lambrechts

Schepers

et al. 2019

EMBO Mol Med

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PKAN, CoPAN, MePAN, and PDH‐E2 deficiency share key phenotypic features but harbor defects in distinct metabolic processes. Selective damage to the globus pallidus occurs in these genetic neurodegenerative diseases, which arise from defects in CoA biosynthesis (PKAN, CoPAN), protein lipoylation (MePAN), and pyruvate dehydrogenase activity (PDH‐E2 deficiency). Overlap of their clinical features suggests a common molecular etiology, the identification of which is required to understand their pathophysiology and design treatment strategies. We provide evidence that CoA‐dependent activation of mitochondrial acyl carrier protein (mtACP) is a possible process linking these diseases through its effect on PDH activity. CoA is the source for the 4′‐phosphopantetheine moiety required for the posttranslational 4′‐phosphopantetheinylation needed to activate specific proteins. We show that impaired CoA homeostasis leads to decreased 4′‐phosphopantetheinylation of mtACP. This results in a decrease of the active form of mtACP, and in turn a decrease in lipoylation with reduced activity of lipoylated proteins, including PDH. Defects in the steps of a linked CoA‐mtACP‐PDH pathway cause similar phenotypic abnormalities. By chemically and genetically re‐activating PDH, these phenotypes can be rescued, suggesting possible treatment strategies for these diseases.

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Mitochondrial fatty acid synthesis, fatty acids and mitochondrial physiology

Cited by 125 publications

References 122 publications

Genome‐wide characterization of Phytophthora infestans metabolism: a systems biology approach

Genome‐wide characterization of Phytophthora infestans metabolism: a systems biology approach

Fatty Acid Biosynthesis: Chain‐Length Regulation and Control

CoA‐dependent activation of mitochondrial acyl carrier protein links four neurodegenerative diseases

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