scholarly journals Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

2016 ◽  
Vol 36 (2) ◽  
Author(s):  
Abena Nsiah-Sefaa ◽  
Matthew McKenzie
Keyword(s):  
Fatty Acid ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Disease ◽  
Metabolic Pathways ◽  
Live Births ◽  
Mitochondrial Fatty Acid ◽  
Physical Interactions ◽  
The Brain ◽  
Combined Defects

Mitochondria provide the main source of energy to eukaryotic cells, oxidizing fats and sugars to generate ATP. Mitochondrial fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two metabolic pathways which are central to this process. Defects in these pathways can result in diseases of the brain, skeletal muscle, heart and liver, affecting approximately 1 in 5000 live births. There are no effective therapies for these disorders, with quality of life severely reduced for most patients. The pathology underlying many aspects of these diseases is not well understood; for example, it is not clear why some patients with primary FAO deficiencies exhibit secondary OXPHOS defects. However, recent findings suggest that physical interactions exist between FAO and OXPHOS proteins, and that these interactions are critical for both FAO and OXPHOS function. Here, we review our current understanding of the interactions between FAO and OXPHOS proteins and how defects in these two metabolic pathways contribute to mitochondrial disease pathogenesis.

scholarly journals Determining the Bioenergetic Capacity for Fatty Acid Oxidation in the Mammalian Nervous System

2020 ◽  
Vol 40 (10) ◽  
Author(s):  
Cory J. White ◽  
Jieun Lee ◽  
Joseph Choi ◽  
Tiffany Chu ◽  
Susanna Scafidi ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Nervous System ◽  
Fatty Acid ◽  
Conditional Knockout ◽  
Mammalian Brain ◽  
Metabolic State ◽  
Peripheral Tissues ◽  
Mitochondrial Fatty Acid ◽  
The Brain ◽  
Long Chain

ABSTRACT The metabolic state of the brain can greatly impact neurologic function. Evidence of this includes the therapeutic benefit of a ketogenic diet in neurologic diseases, including epilepsy. However, brain lipid bioenergetics remain largely uncharacterized. The existence, capacity, and relevance of mitochondrial fatty acid β-oxidation (FAO) in the brain are highly controversial, with few genetic tools available to evaluate the question. We have provided evidence for the capacity of brain FAO using a pan-brain-specific conditional knockout (KO) mouse incapable of FAO due to the loss of carnitine palmitoyltransferase 2, the product of an obligate gene for FAO (CPT2B−/−). Loss of central nervous system (CNS) FAO did not result in gross neuroanatomical changes or systemic differences in metabolism. Loss of CPT2 in the brain did not result in robustly impaired behavior. We demonstrate by unbiased and targeted metabolomics that the mammalian brain oxidizes a substantial quantity of long-chain fatty acids in vitro and in vivo. Loss of CNS FAO results in robust accumulation of long-chain acylcarnitines in the brain, suggesting that the mammalian brain mobilizes fatty acids for their oxidation, irrespective of diet or metabolic state. Together, these data demonstrate that the mammalian brain oxidizes fatty acids under normal circumstances with little influence from or on peripheral tissues.

scholarly journals Quantifying the patterns of metabolic plasticity and heterogeneity along the epithelial-hybrid-mesenchymal spectrum in cancer

2021 ◽  
Author(s):  
Srinath Muralidharan ◽  
Sarthak Sahoo ◽  
Aryamaan Saha ◽  
Sanjay Chandran ◽  
Sauma Suvra Majumdar ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Metabolic Pathways ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Acid Oxidation ◽  
Mesenchymal Transition ◽  
Metabolic Plasticity ◽  
Cell Data

Cancer metastasis is the leading cause of cancer-related mortality and the process of Epithelial to Mesenchymal Transition (EMT) is crucial for cancer metastasis. Either a partial or complete EMT have been reported to influence the metabolic plasticity of cancer cells in terms of switching among oxidative phosphorylation, fatty acid oxidation and glycolysis pathways. However, a comprehensive analysis of these major metabolic pathways their associations with EMT across different cancers is lacking. Here, we analyse more than 180 cancer cell datasets and show diverse associations of these metabolic pathways with the EMT status of cancer cells. Our bulk data analysis shows that EMT generally positively correlates with glycolysis but negatively with oxidative phosphorylation and fatty acid metabolism. These correlations are also consistent at the level of their molecular master regulators, namely AMPK and HIF1α. Yet, these associations are shown to not be universal. Analysis of single-cell data of EMT induction shows dynamic changes along the different axes of metabolic pathways, consistent with general trends seen in bulk samples. Together, our results reveal underlying patterns of metabolic plasticity and heterogeneity as cancer cells traverse through the epithelial-hybrid-mesenchymal spectrum of states.

scholarly journals Signatures of mito-nuclear climate adaptation in a warbler species complex

2020 ◽  
Author(s):  
Silu Wang ◽  
Madelyn J. Ore ◽  
Else K. Mikkelsen ◽  
Julie Lee-Yaw ◽  
Sievert Rohwer ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Metabolic Pathways ◽  
Species Complex ◽  
Acid Metabolism ◽  
Climate Adaptation ◽  
Climatic Conditions ◽  
Secondary Contact ◽  
Mitochondrial Fatty Acid ◽  
Genetic Patterns

AbstractMitochondrial (mtDNA) and nuclear (nDNA) genes interact to govern metabolic pathways of mitochondria. When differentiated populations interbreed at secondary contact, incompatibilities between mtDNA of one population and nDNA of the other could result in low fitness of hybrids. Hermit Warblers (S. occidentalis abbreviated as HEWA) and inland Townsend’s Warblers (Setophaga townsendi, abbreviated as i-TOWA) exhibit distinct mtDNA haplotypes and a few nDNA regions of high differentiation, whereas coastal TOWA (c-TOWA) displays a mix of these genetic patterns consistent with ancient hybridization of HEWA and i-TOWA. Of the few highly-differentiated nDNA regions between i-TOWA and HEWA, two of these regions (on chromosome 5 and Z, respectively) are also differentiated between c-TOWA and i-TOWA, similar to the mtDNA pattern. These two nDNA regions are associated with mitochondrial fatty acid metabolism. Moreover, these nDNA regions are correlated with mtDNA ancestries among sites, a pattern consistent with mito-nuclear co-adaptation. Such mito-nuclear coevolution might be driven by climate-related selection, because the mito-nuclear ancestry is correlated with climatic conditions among sampling sites. These results suggest that cryptic differentiation in this species complex has been shaped by climate-correlated adaptation associated with mito-nuclear fatty acid metabolism.

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