Mitochondrial fatty acid synthesis and respiration

Hiltunen, J. Kalervo; Autio, Kaija J.; Schonauer, Melissa S.; Kursu, V. A. Samuli; Dieckmann, Carol L.; Kastaniotis, Alexander J.

doi:10.1016/j.bbabio.2010.03.006

Cited by 121 publications

(125 citation statements)

References 83 publications

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“…The connection between ACP and Fe-S cluster biosynthesis is consistent with a previously proposed model in which mtFAS plays a regulatory role in oxidative respiration (14,15). Experimental evidence supports a role of ACP-associated fatty acids in the processing of mitochondrial RNA and expression of the respiratory complexes (14,70), synthesis of Fe-S cluster cofactors (1), and achieving the mature protein assembly and active conformation for the respiratory complexes (3,23).…”

Section: Discussionsupporting

confidence: 72%

“…Thus, it appears from our results and the work of others that the evolutionarily conserved pathways of Fe-S cluster biosynthesis, oxidative phosphorylation, and mtFAS have been connected by LYR proteins and their respective acyl-ACP associations. The mechanistic role for the acyl-chain is still unclear; however, it is possible that acyl-ACP acts as a metabolic sensor for the mitochondria by reporting the abundance of acetyl-CoA, as proposed previously (15), and allowing mtFAS to coordinate the expression, Fe-S cofactor assembly, and activity of the respiratory complexes. Overall, the cross-communication between biosynthetic and primary metabolic pathways through the utilization of LYR-acyl-ACP interactions is a potential and exciting avenue of regulation that warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…ACP operates in the mitochondrial fatty acid synthesis (mtFAS) pathway to synthesize fatty acids using a 4′-phosphopantethiene (4′-PPT) prosthetic group covalently attached to a serine residue on ACP. Acyl intermediates are linked by a thioester bond and shuttled between fatty acid biosynthetic enzymes to generate medium and long chain fatty acids (12)(13)(14)(15). One of the best known functions of the mtFAS pathway is to generate octanoyl-ACP, which is required for lipoic acid biosynthesis.…”

mentioning

confidence: 99%

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Structure of human Fe–S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP–ISD11 interactions

Cory

Vranken

Brignole

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

141

228

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In eukaryotes, sulfur is mobilized for incorporation into multiple biosynthetic pathways by a cysteine desulfurase complex that consists of a catalytic subunit (NFS1), LYR protein (ISD11), and acyl carrier protein (ACP). This NFS1-ISD11-ACP (SDA) complex forms the core of the iron-sulfur (Fe-S) assembly complex and associates with assembly proteins ISCU2, frataxin (FXN), and ferredoxin to synthesize Fe-S clusters. Here we present crystallographic and electron microscopic structures of the SDA complex coupled to enzyme kinetic and cell-based studies to provide structure-function properties of a mitochondrial cysteine desulfurase. Unlike prokaryotic cysteine desulfurases, the SDA structure adopts an unexpected architecture in which a pair of ISD11 subunits form the dimeric core of the SDA complex, which clarifies the critical role of ISD11 in eukaryotic assemblies. The different quaternary structure results in an incompletely formed substrate channel and solvent-exposed pyridoxal 5′-phosphate cofactor and provides a rationale for the allosteric activator function of FXN in eukaryotic systems. The structure also reveals the 4′-phosphopantetheine-conjugated acyl-group of ACP occupies the hydrophobic core of ISD11, explaining the basis of ACP stabilization. The unexpected architecture for the SDA complex provides a framework for understanding interactions with acceptor proteins for sulfur-containing biosynthetic pathways, elucidating mechanistic details of eukaryotic Fe-S cluster biosynthesis, and clarifying how defects in Fe-S cluster assembly lead to diseases such as Friedreich's ataxia. Moreover, our results support a lock-and-key model in which LYR proteins associate with acyl-ACP as a mechanism for fatty acid biosynthesis to coordinate the expression, Fe-S cofactor maturation, and activity of the respiratory complexes.ron-sulfur (Fe-S) clusters are protein cofactors and are required for critical biological processes such as oxidative respiration, nitrogen fixation, and photosynthesis. The iron-sulfur cluster (ISC) biosynthetic pathway, which is found in most prokaryotes and in the mitochondrial matrix of eukaryotes, is responsible for the synthesis of Fe-S clusters and distribution of these cofactors to the appropriate target proteins. Despite the homology between analogous components of the prokaryotic and eukaryotic ISC pathways, there are key unexplained differences, such as the requirement of the LYR protein ISD11 and acyl carrier protein (ACP) for function in eukaryotic but not prokaryotic ISC systems (1, 2).Mitochondrial LYR proteins are members of a recently identified superfamily that are characterized by their small size (10-22 kDa), high positive charge, invariant Phe residue, and eponymous LeuTyr-Arg (LYR) motif near their N terminus (3). LYR proteins function as subunits or assembly factors for respiratory complexes I, II, III, and V. Human LYRM4, also known as ISD11, is critical for the function of the Fe-S assembly complex (4-9), whereas LYRM8, a key maturation factor for mitochondrial complex II, ...

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Structure of human Fe–S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP–ISD11 interactions

Cory

Vranken

Brignole

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

141

228

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“…Under these conditions, the energy output of mitochondria decreases [150] and limits the efficiency of pathways that rely on acetyl-CoA as a substrate (e.g. longchain fatty acid biosynthesis [151]). For organisms adapting to hypoxia, acquiring an NADH-insensitive pyruvate-oxidizing enzyme such as PFO would be selectively advantageous.…”

Section: (C) a New Scenariomentioning

confidence: 99%

Diversity and origins of anaerobic metabolism in mitochondria and related organelles

Stairs

Leger

Roger

2015

Phil. Trans. R. Soc. B

130

172

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One contribution of 17 to a theme issue 'Eukaryotic origins: progress and challenges'. Across the diversity of life, organisms have evolved different strategies to thrive in hypoxic environments, and microbial eukaryotes ( protists) are no exception. Protists that experience hypoxia often possess metabolically distinct mitochondria called mitochondrion-related organelles (MROs). While there are some common metabolic features shared between the MROs of distantly related protists, these organelles have evolved independently multiple times across the breadth of eukaryotic diversity. Until recently, much of our knowledge regarding the metabolic potential of different MROs was limited to studies in parasitic lineages. Over the past decade, deep-sequencing studies of free-living anaerobic protists have revealed novel configurations of metabolic pathways that have been co-opted for life in low oxygen environments. Here, we provide recent examples of anaerobic metabolism in the MROs of free-living protists and their parasitic relatives. Additionally, we outline evolutionary scenarios to explain the origins of these anaerobic pathways in eukaryotes.

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“…2). Intriguingly, the synthesis of lipoic acid is dependent on an Acp1-derived octanoyl fatty acyl chain, an aspect that links the early ISC machinery and the Fe/S target protein lipoic acid synthase (45). The combined defects in protein lipoylation and the respiratory chain complexes are a hallmark of Fe/S diseases, especially in the so-called multiple mitochondrial dysfunction syndromes, and are now used for diagnostic purposes (7,9).…”

Section: Synthesis and Trafficking Of The [4fe-4s] Cluster In Mitochomentioning

confidence: 99%

Iron–sulfur cluster biogenesis and trafficking in mitochondria

Braymer

Lill

2017

Journal of Biological Chemistry

314

293

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The biogenesis of iron-sulfur (Fe/S) proteins in eukaryotes is a multistage, multicompartment process that is essential for a broad range of cellular functions, including genome maintenance, protein translation, energy conversion, and the antiviral response. Genetic and cell biological studies over almost 2 decades have revealed some 30 proteins involved in the synthesis of cellular [2Fe-2S] and [4Fe-4S] clusters and their incorporation into numerous apoproteins. Mechanistic aspects of Fe/S protein biogenesis continue to be elucidated by biochemical and ultrastructural investigations. Here, we review recent developments in the pursuit of constructing a comprehensive model of Fe/S protein assembly in the mitochondrion. Ubiquitous iron-sulfur clusters and their synthesis: an overviewIron-sulfur (Fe/S) 2 clusters are inorganic cofactors that are essential for the proper functioning of virtually all biological cells (1). The chemical versatility of these clusters is utilized in fundamental life processes such as energy production, metabolic conversions, DNA maintenance, gene expression regulation, protein translation, and the antiviral response ( Fig. 1) (2-4). In eukaryotes, Fe/S proteins are found in or associated with the mitochondrion, endoplasmic reticulum, cytosol, and the nucleus. These cofactors participate in electron transfer reactions, Lewis acid catalysis, transfer of sulfur atoms, or facilitating structural roles (5, 6). Although the activities of some Fe/S proteins are dispensable for cell survival under certain conditions, for example fungal Fe/S enzymes in the metabolism of amino acids, others such as Fe/S proteins involved in DNA maintenance or protein translation are essential for cell viability (Fig. 1). The growing number of diseases that implicate Fe/S proteins or their assembly factors illustrates the essentiality of the various functions of these protein cofactors (7-9). The phenotypes associated with these "Fe/S diseases" and the in vivo work in model systems such as Saccharomyces cerevisiae and human cell culture have led to a mechanistic model of eukaryotic Fe/S protein biogenesis, in which the sequence of events required for proper synthesis and trafficking of Fe/S clusters has been elucidated (2). This model has been invaluable to diagnosing new mitochondrial disorders, and its continued advancement will enhance the ability for early diagnosis (10 -13). The focus of this review will be on the latest developments of the functional and mechanistic aspects that have advanced the model of mitochondrial Fe/S protein biogenesis.Cells typically maintain a strict balance of iron and sulfide ion concentrations due to their damaging redox reactions when present in excess (14, 15). The cell also uses a complex biosynthetic system to ensure that the sometimes redox-sensitive and labile Fe/S clusters are assembled correctly, trafficked to specific target apoproteins, and remain protected during these processes. This cellular control is exemplified by the 18 known "Fe/S cluster assembly" (ISC) proteins...

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Mitochondrial fatty acid synthesis and respiration

Cited by 121 publications

References 83 publications

Structure of human Fe–S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP–ISD11 interactions

Structure of human Fe–S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP–ISD11 interactions

Diversity and origins of anaerobic metabolism in mitochondria and related organelles

Iron–sulfur cluster biogenesis and trafficking in mitochondria

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