scholarly journals A conserved mammalian mitochondrial isoform of acetyl-CoA carboxylase ACC1 provides the malonyl-CoA essential for mitochondrial biogenesis in tandem with ACSF3

2017 ◽  
Vol 474 (22) ◽  
pp. 3783-3797 ◽  
Author(s):  
Geoffray Monteuuis ◽  
Fumi Suomi ◽  
Juha M. Kerätär ◽  
Ali J. Masud ◽  
Alexander J. Kastaniotis
Keyword(s):  
Lipoic Acid ◽  
Mitochondrial Biogenesis ◽  
Metabolic Regulation ◽  
Mitochondrial Respiratory Chain ◽  
Acid Synthesis ◽  
Malonyl Coa ◽  
Mitochondrial Fatty Acid ◽  
Mitochondrial Enzyme Complexes ◽  
Mouse Cells ◽  
And Function

Mitochondrial fatty acid synthesis (mtFAS) is a highly conserved pathway essential for mitochondrial biogenesis. The mtFAS process is required for mitochondrial respiratory chain assembly and function, synthesis of the lipoic acid cofactor indispensable for the function of several mitochondrial enzyme complexes and essential for embryonic development in mice. Mutations in human mtFAS have been reported to lead to neurodegenerative disease. The source of malonyl-CoA for mtFAS in mammals has remained unclear. We report the identification of a conserved vertebrate mitochondrial isoform of ACC1 expressed from an ACACA transcript splicing variant. A specific knockdown (KD) of the corresponding transcript in mouse cells, or CRISPR/Cas9-mediated inactivation of the putative mitochondrial targeting sequence in human cells, leads to decreased lipoylation and mitochondrial fragmentation. Simultaneous KD of ACSF3, encoding a mitochondrial malonyl-CoA synthetase previously implicated in the mtFAS process, resulted in almost complete ablation of protein lipoylation, indicating that these enzymes have a redundant function in mtFAS. The discovery of a mitochondrial isoform of ACC1 required for lipoic acid synthesis has intriguing consequences for our understanding of mitochondrial disorders, metabolic regulation of mitochondrial biogenesis and cancer.

scholarly journals Impact of Mitochondrial Fatty Acid Synthesis on Mitochondrial Biogenesis

2018 ◽  
Vol 28 (20) ◽  
pp. R1212-R1219 ◽  
Author(s):  
Sara M. Nowinski ◽  
Jonathan G. Van Vranken ◽  
Katja K. Dove ◽  
Jared Rutter
Keyword(s):  
Fatty Acid ◽  
Mitochondrial Biogenesis ◽  
Fatty Acid Synthesis ◽  
Acid Synthesis ◽  
Mitochondrial Fatty Acid

scholarly journals Intersection of RNA Processing and the Type II Fatty Acid Synthesis Pathway in Yeast Mitochondria

2008 ◽  
Vol 28 (21) ◽  
pp. 6646-6657 ◽  
Author(s):  
Melissa S. Schonauer ◽  
Alexander J. Kastaniotis ◽  
J. Kalervo Hiltunen ◽  
Carol L. Dieckmann
Keyword(s):  
Fatty Acid ◽  
Lipoic Acid ◽  
Rna Processing ◽  
Mitochondrial Gene ◽  
Rnase P ◽  
Acid Synthesis ◽  
Mitochondrial Enzymes ◽  
Type Ii ◽  
Mitochondrial Fatty Acid ◽  
Fas Ii

ABSTRACT Distinct metabolic pathways can intersect in ways that allow hierarchical or reciprocal regulation. In a screen of respiration-deficient Saccharomyces cerevisiae gene deletion strains for defects in mitochondrial RNA processing, we found that lack of any enzyme in the mitochondrial fatty acid type II biosynthetic pathway (FAS II) led to inefficient 5′ processing of mitochondrial precursor tRNAs by RNase P. In particular, the precursor containing both RNase P RNA (RPM1) and tRNAPro accumulated dramatically. Subsequent Pet127-driven 5′ processing of RPM1 was blocked. The FAS II pathway defects resulted in the loss of lipoic acid attachment to subunits of three key mitochondrial enzymes, which suggests that the octanoic acid produced by the pathway is the sole precursor for lipoic acid synthesis and attachment. The protein component of yeast mitochondrial RNase P, Rpm2, is not modified by lipoic acid in the wild-type strain, and it is imported in FAS II mutant strains. Thus, a product of the FAS II pathway is required for RNase P RNA maturation, which positively affects RNase P activity. In addition, a product is required for lipoic acid production, which is needed for the activity of pyruvate dehydrogenase, which feeds acetyl-coenzyme A into the FAS II pathway. These two positive feedback cycles may provide switch-like control of mitochondrial gene expression in response to the metabolic state of the cell.

scholarly journals Defects in mitochondrial fatty acid synthesis result in failure of multiple aspects of mitochondrial biogenesis inSaccharomyces cerevisiae

2013 ◽  
Vol 90 (4) ◽  
pp. 824-840 ◽  
Author(s):  
V. A. Samuli Kursu ◽  
Laura P. Pietikäinen ◽  
Flavia Fontanesi ◽  
Mari J. Aaltonen ◽  
Fumi Suomi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Mitochondrial Biogenesis ◽  
Fatty Acid Synthesis ◽  
Acid Synthesis ◽  
Mitochondrial Fatty Acid

scholarly journals Mitochondrial fatty acid synthesis is required for normal mitochondrial morphology and function in Trypanosoma brucei

2008 ◽  
Vol 67 (5) ◽  
pp. 1125-1142 ◽  
Author(s):  
Jennifer L. Guler ◽  
Eva Kriegova ◽  
Terry K. Smith ◽  
Julius Lukeš ◽  
Paul T. Englund
Keyword(s):  
Fatty Acid ◽  
Trypanosoma Brucei ◽  
Fatty Acid Synthesis ◽  
Acid Synthesis ◽  
Mitochondrial Morphology ◽  
Mitochondrial Fatty Acid ◽  
And Function

scholarly journals Genetic dissection of the mitochondrial lipoylation pathway in yeast

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Laura P. Pietikäinen ◽  
M. Tanvir Rahman ◽  
J. Kalervo Hiltunen ◽  
Carol L. Dieckmann ◽  
Alexander J. Kastaniotis
Keyword(s):  
Lipoic Acid ◽  
Model Organism ◽  
Acid Synthesis ◽  
Fatty Acyl ◽  
Model System ◽  
Genetic Dissection ◽  
Post Translational Modification ◽  
Mitochondrial Fatty Acid ◽  
Glycine Cleavage

Abstract Background Lipoylation of 2-ketoacid dehydrogenases is essential for mitochondrial function in eukaryotes. While the basic principles of the lipoylation processes have been worked out, we still lack a thorough understanding of the details of this important post-translational modification pathway. Here we used yeast as a model organism to characterize substrate usage by the highly conserved eukaryotic octanoyl/lipoyl transferases in vivo and queried how amenable the lipoylation system is to supplementation with exogenous substrate. Results We show that the requirement for mitochondrial fatty acid synthesis to provide substrates for lipoylation of the 2-ketoacid dehydrogenases can be bypassed by supplying the cells with free lipoic acid (LA) or octanoic acid (C8) and a mitochondrially targeted fatty acyl/lipoyl activating enzyme. We also provide evidence that the S. cerevisiae lipoyl transferase Lip3, in addition to transferring LA from the glycine cleavage system H protein to the pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KGD) E2 subunits, can transfer this cofactor from the PDH complex to the KGD complex. In support of yeast as a model system for human metabolism, we demonstrate that the human octanoyl/lipoyl transferases can substitute for their counterparts in yeast to support respiratory growth and protein lipoylation. Like the wild-type yeast enzyme, the human lipoyl transferase LIPT1 responds to LA supplementation in the presence of the activating enzyme LplA. Conclusions In the yeast model system, the eukaryotic lipoylation pathway can use free LA and C8 as substrates when fatty/lipoic acid activating enzymes are targeted to mitochondria. Lip3 LA transferase has a wider substrate specificity than previously recognized. We show that these features of the lipoylation mechanism in yeast are conserved in mammalian mitochondria. Our findings have important implications for the development of effective therapies for the treatment of LA or mtFAS deficiency-related disorders.

scholarly journals Genetic dissection of the mitochondrial lipoylation pathway in yeast

2020 ◽  
Author(s):  
Laura P. Pietikäinen ◽  
M. Tanvir Rahman ◽  
J. Kalervo Hiltunen ◽  
Carol L. Dieckmann ◽  
Alexander J. Kastaniotis
Keyword(s):  
Lipoic Acid ◽  
Model Organism ◽  
Acid Synthesis ◽  
Fatty Acyl ◽  
Model System ◽  
Genetic Dissection ◽  
Post Translational Modification ◽  
Mitochondrial Fatty Acid ◽  
Glycine Cleavage

ABSTRACTBackgroundLipoylation of 2-ketoacid dehydrogenases is essential for mitochondrial function in eukaryotes. While the basic principles of the lipoylation processes have been worked out, we still lack a thorough understanding of the details of this important post-translational modification pathway. Here we used yeast as a model organism to characterize substrate usage by the highly conserved eukaryotic octanoyl/lipoyl transferases in vivo and queried how amenable the lipoylation system is to supplementation with exogenous substrate.ResultsWe show that the requirement for mitochondrial fatty acid synthesis to provide substrates for lipoylation of the 2-ketoacid dehydrogenases can be bypassed by supplying the cells with free lipoic acid (LA) or octanoic acid (C8) and a mitochondrially targeted fatty acyl/lipoyl activating enzyme. We also provide evidence that the S. cerevisiae lipoyl transferase Lip3, in addition to transferring LA from the glycine cleavage system H protein to the pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KGD) E2 subunits, can transfer this cofactor from the PDH complex to the KGD complex. In support of yeast as a model system for human metabolism, we demonstrate that the human octanoyl/lipoyl transferases can substitute for their counterparts in yeast to support respiratory growth and protein lipoylation. Like the wild-type yeast enzyme, the human lipoyl transferase LIPT1 responds to LA supplementation in the presence of the activating enzyme LplA.ConclusionsIn the yeast model system, the eukaryotic lipoylation pathway can use free LA and C8 as substrates when fatty/lipoic acid activating enzymes are targeted to mitochondria. Lip3 LA transferase has a wider substrate specificity than previously recognized. We show that these features of the lipoylation mechanism in yeast are conserved in mammalian mitochondria. Our findings have important implications for the development of effective therapies for the treatment of LA or mtFAS deficiency-related disorders.

scholarly journals PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer

Oncogene ◽  
2021 ◽  
Vol 40 (13) ◽  
pp. 2355-2366
Author(s):  
Laura C. A. Galbraith ◽  
Ernest Mui ◽  
Colin Nixon ◽  
Ann Hedley ◽  
David Strachan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mitochondrial Biogenesis ◽  
Nuclear Export ◽  
Epithelial To Mesenchymal Transition ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Serine Threonine Kinase ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mesenchymal Transition ◽  
And Function

AbstractPeroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.

scholarly journals Embryonic Origin and Subclonal Evolution of Tumor-Associated Macrophages Imply Preventive Care for Cancer

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 903
Author(s):  
Xiao-Mei Zhang ◽  
De-Gao Chen ◽  
Shengwen Calvin Li ◽  
Bo Zhu ◽  
Zhong-Jun Li
Keyword(s):  
Metabolic Regulation ◽  
Transcriptional Profiling ◽  
Tumor Development ◽  
Metabolic Reprogramming ◽  
Cancer Therapies ◽  
Functional Heterogeneity ◽  
Tumor Associated Macrophages ◽  
Metabolic Remodeling ◽  
And Function ◽  
Mapping Models

Macrophages are widely distributed in tissues and function in homeostasis. During cancer development, tumor-associated macrophages (TAMs) dominatingly support disease progression and resistance to therapy by promoting tumor proliferation, angiogenesis, metastasis, and immunosuppression, thereby making TAMs a target for tumor immunotherapy. Here, we started with evidence that TAMs are highly plastic and heterogeneous in phenotype and function in response to microenvironmental cues. We pointed out that efforts to tear off the heterogeneous “camouflage” in TAMs conduce to target de facto protumoral TAMs efficiently. In particular, several fate-mapping models suggest that most tissue-resident macrophages (TRMs) are generated from embryonic progenitors, and new paradigms uncover the ontogeny of TAMs. First, TAMs from embryonic modeling of TRMs and circulating monocytes have distinct transcriptional profiling and function, suggesting that the ontogeny of TAMs is responsible for the functional heterogeneity of TAMs, in addition to microenvironmental cues. Second, metabolic remodeling helps determine the mechanism of phenotypic and functional characteristics in TAMs, including metabolic bias from macrophages’ ontogeny in macrophages’ functional plasticity under physiological and pathological conditions. Both models aim at dissecting the ontogeny-related metabolic regulation in the phenotypic and functional heterogeneity in TAMs. We argue that gleaning from the single-cell transcriptomics on subclonal TAMs’ origins may help understand the classification of TAMs’ population in subclonal evolution and their distinct roles in tumor development. We envision that TAM-subclone-specific metabolic reprogramming may round-up with future cancer therapies.

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