How does acetyl coa get into the mitochondria

Fatty acids are made two carbon atoms at a time. Many of the metabolic processes taking place in cells, including the breakdown of carbohydrates for energy, result in the production of a two-carbon molecular fragment called an acetyl group CH 3 -CO-. This is a very tiny molecular fragment that could easily get lost in the soup of similar tiny molecules which pack the cytoplasm of all metabolically active cells, so it is joined to a much larger molecule called CoEnzyme A CoA.

This hybrid molecule, acetyl-CoA , is a central player in the synthesis of all fatty acids. Acetyl-CoA is first made in the mitochondria either by the removal of hydrogen from a molecule pyruvate or by the oxidation of other fatty acids. This is a delicate balancing act.

When the cell needs lots of ATP energy, all the pyruvate and oxidized fatty acids are broken down further in the tricarboxylic acid TCA cycle so as to make more and more ATP. However, if the need for energy supplies decreases, the cells switch off these breakdown reactions and switch over to those metabolic pathways that join acetyl units together to form fatty acids, lipids and fat. These lipids are then stored and used as long-term fuel supplies as and when they are needed.

However, all of these two-carbon acetyl units are in the wrong place. Before they can be used in fatty acid synthesis, they have to be moved into the cytoplasm of the cell, where the fatty acids will be made. Acetyl-CoA is moved through the mitochondrial membrane, and enters the cytoplasm of the cell, as the molecule citrate. This pathway requires that C n-3 would be desaturated at position 4 by an acyl-CoA-dependent delta4-desaturase to form C n Several studies have shown that mammals do not possess such a delta4-desaturase.

Instead, a carbon n-3 fatty acid is first synthesized which is then desaturated at position six to produce C n-3 followed by one round of beta-oxidation in the peroxisome with C n-3 as final product see Figure 7.

The CCoA produced in peroxisomes may either undergo continued beta-oxidation in peroxisomes and subsequently in mitochondria or be exported out of the peroxisome for incorporation into lipids in the endoplasmic reticulum. The exact mechanism by which DHA is exported from the peroxisomes either as coenzyme A ester or as free acid has not been deduced sofar. Figure 7. Schematic diagram showing the key role of peroxisomes in the formation of C n Doxosahexaenoic acid is synthesized from C n-3 which first undergoes a number of elongation and desaturation steps in the endoplasmic reticulum to produce CCoA which is then transported to the peroxisome and imported via a mechanism not yet resolved.

Within peroxisomes CCoA undergoes one cycle of beta-oxidation to produce the corresponding CCoA which can then be exported out of the peroxisome for subsequent incorporation into lipids in the endoplasmic reticulum or may undergo additional sequential rounds of oxidation in peroxisomes and mitochondria. See text for more detailed information. Peroxisomes also play an indispensable role in the biosynthesis of the primary bile acids cholic acid and chenodeoxycholic acid. The underlying basis for the obligatory role of peroxisomes in bile acid formation, resides in the fact that the two bile acid intermediates, i.

Figure 8. Schematic diagram showing the unique and important role of peroxisomes in the formation of the primary bile acids cholic acid and deoxycholic acid. In order to allow oxidation of 3-methyl-FAs, these FAs first need to undergo one cycle of alpha-oxidation thereby converting the 3-methyl-FA into a 2-methyl-FA which can then be beta-oxidized Wanders et al.

Alternatively, 3-methyl-FAs may be oxidized via the omega end so that phytanic acid is actually chain-shortened from the omega-end see Wanders et al. The best known FA undergoing alpha-oxidation, is phytanic acid 3,7,11,tetramethylhexadecanoic acid as concluded from observations on a rare disease called Refsum disease in which alpha-oxidation is blocked due to a genetic deficiency of the enzyme phytanoyl-CoA 2-hydroxylase encoded by PHYH.

Phytanic acid is strictly derived from dietary sources and cannot be synthesized de novo. Although not well-studied, the general notion is that phytanic acid is transported throughout the body via the blood in its free as well as esterified form. Indeed, in plasma phytanic acid has been identified in triglycerides but also in other lipid species.

According to Wierzbicki et al. Hydrolysis of LDL-particles after receptor mediated uptake into cells within lysosomes would then release the phytanic acid into the cytosol.

The fact that there are multiple acyl-CoA synthetases able to convert phytanic acid into phytanoyl-CoA see Wanders et al. This implies that phytanoyl-CoA is the most likely substrate to be transported across the peroxisomal membrane. Figure 9. Functional interplay between mitochondria and peroxisomes in the alpha-oxidation of phytanic acid. Once inside the peroxisome interior, phytanoyl-CoA is hydroxylated by the enzyme phytanoyl-CoA 2-hydroxylase first identified by Mihalik et al. The enzyme involved belongs to the group of 2-oxoglutarate-dependent dioxygenases and the hydroxylation of the substrate is driven by 2-oxoglutarate and molecular oxygen with succinate and CO 2 as products Mukherji et al.

Subsequently, the enzyme 2-hydroxyacyl-CoA lyase HACL cleaves 2-hydroxyphytanoyl-CoA, and a range of other 2-hydroxy acyl-CoAs in fact, between the first and second carbon atom to produce formyl-CoA plus the aldehyde pristanal in case of phytanic acid alpha-oxidation Foulon et al.

This aldehyde is then converted into the corresponding acid pristanic acid. Available evidence holds that peroxisomes do contain aldehyde dehydrogenase activity as shown for pristanal by Jansen et al. The true identity of this enzyme activity has not been settled definitively.

Whether FALDH-V is truly the enzyme responsible for the pristanal dehydrogenase activity in peroxisomes remains doubtful, however, for various reasons including the fact that FALDH-V appears to be a membrane-bound enzyme with its catalytic domain exposed to the cytosol, whereas the peroxisomal pristanal dehydrogenase activity is catalyzed by a soluble matrix enzyme Jansen et al. In line with these results, phytanic acid does not accumulate in SLS-patients. Figure 9 depicts the organization of the alpha-oxidation system in peroxisomes as envisaged right now with phytanoyl-CoA 2-hydroxylase, HACL, and also the putative pristanal dehydrogenase all localized in the matrix of the peroxisome.

Furthermore, constant supply of 2-oxoglutarate is required, coupled to the removal of succinate. Both 2-oxoglutarate and succinate can probably move freely through the peroxisomal membrane via the peroxisomal porine PXMP2. Since succinate is a 4-carbon molecule, whereas 2-oxoglutarate has 5-carbon atoms, reconversion of succinate back into 2-oxoglutarate can only be achieved via one of the carboxylases or some other mechanism.

A possible role for one of the four known carboxylases, including pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase, and methylmalonyl-CoA carboxylase is hard to envisage. However, conversion of succinate back into 2-oxoglutarate can also occur in the mitochondrion by using part of the citric acid cycle and in particular the citrate synthase reaction which can turn a C4-molecule like oxaloacetate into the 6-carbon molecule citrate.

The mechanism would then be that succinate enters the mitochondrion via the mitochondrial dicarboxylate carrier and is converted back into 2-oxoglutarate via the concerted action of succinate dehydrogenase, fumarase, malate dehydrogenase, citrate synthase, and NAD-linked isocitrate dehydrogenase followed by export of 2-oxoglutarate via the mitochondrial carrier specific for 2-oxoglutarate see Figure 9.

With respect to one of the other products of alpha-oxidation, i. Formic acid can be degraded via two pathways including: 1. Finally, the CoA released from formyl-CoA could be used to convert pristanic acid to pristanoyl-CoA as described above. Figure 9 shows the final scheme in which the considerations above have been incorporated and used to construct a feasible model.

In humans the enzyme alanine glyoxylate aminotransferase AGXT is the principal enzyme involved in the detoxification of glyoxylate, is strictly peroxisomal in human liver Danpure and Jennings, and a deficiency of this enzyme causes hyperoxaluria type 1 Danpure et al. The product of the AGXT reaction in peroxisomes is pyruvate which needs to be reconverted into alanine via different transaminases localized in the cytosol or degraded in the mitochondrion via the enzyme pyruvate dehydrogenase, which again shows the interaction of peroxisomes with multiple subcellular compartments including the cytosol and the mitochondrion in the case of glyoxylate metabolism Figure 10 ; Salido et al.

Glycine is further metabolized in mitochondria and broken down via the glycine cleavage enzyme which is made up of four different proteins, named P-, T-, H-, and L-protein see Figure 10 ; Kikuchi et al. Figure The detoxification of glyoxylate in peroxisomes as catalyzed by the enzyme alanine glyoxylate aminotransferase AGXT. It should be noted that much remains to be learned about the metabolic precursors of glyoxylate although glycolate is definitely one of the major sources of glyoxylate with the peroxisomal enzyme 2-hydroxy acid oxidase HAO1; alternative named: glycolate oxidase as the enzyme responsible for the conversion of glycolate to glyoxylate Vignaud et al.

Other known sources of glyoxylate are hydroxyproline Knight et al. Peroxisomes also play an indispensable role in the degradation of a range of amino acids, notably the D-amino acids.

The DAO gene product displays a broad substrate specificity and reacts with a range of neutral and basic D-amino acids including D-serine, D-alanine, and others Krebs, ; Dixon and Kleppe, Mammalian DAO and DDO are presumed to regulate the levels of several endogenous and exogenous D-amino acids including D-serine and D-aspartate in various organs notably the brain.

D-serine for instance binds to the glycine binding site of the N-methyl-D-aspartate NMDA receptor and potentiates glutamatergic neurotransmission in the central nervous system. Several lines of evidence suggest that D-serine plays an important role in the regulation of brain functions by acting as co-agonist for the NMDA receptor and perturbations in D-serine in the nervous system have recently been implicated in the pathophysiology of various neuropsychiatric disorders see Katane et al.

Recent studies have also shown that D-aspartate acts as signaling molecule in nervous and neuroendocrine systems at least in part by binding to the NMDA receptor and, thus plays an important role in the regulation of brain function Katane and Homma, ; Errico et al.

Furthermore, peroxisomes, at least in humans, are the sole site of L-pipecolic acid oxidase activity which is a metabolite derived from lysine Wanders et al. There is currently very little information in literature on the functional interplay between peroxisomes and other subcellular compartments in the oxidation of the various amino acids in humans is concerned. Indeed, peroxisomes contain a large number of ROS-producing enzymes of which the acyl-CoA oxidases are the most abundant being present in virtually all peroxisomes independent of the tissue and cell type involved.

In addition, peroxisomes contain a large network of enzymatic and also non-enzymatic antioxidants that protect the organelle from oxidative damage. Recent work by Fransen and coworkers Wang et al. Peroxisomes play a crucial role in cellular metabolism as exemplified by the different inborn errors of metabolism caused by a deficiency of one of the peroxisomal enzymes Table 1 as reviewed in this paper.

It is also fully clear that the metabolic capabilities of peroxisomes are very much dependent on the functional interplay with other organelles, notably the mitochondrion and endoplasmic reticulum. Although much has been learned about the functional organization of the peroxisome in terms of the enzymes involved and the end-products of peroxisomal metabolism, there are still substantial gaps in our knowledge about peroxisome metabolism.

One other area which has remained relatively unexplored involves the mechanism of transfer of the end products of peroxisome metabolism from the peroxisome to other organelles like the mitochondrion and ER. It is gratifying to see that several recent reports are beginning to shed light on the mechanisms involved in the physical interaction between individual organelles and the proteins involved.

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Wild-type yeast cells 6. Significant differences were observed relative to the control group without methylmercury treatment. The uptake of 14 C-labelled pyruvate into intact mitochondria was measured after treatment with methylmercuric acid in vitro. The imported pyruvate was quantified using a liquid scintillation counter and normalized to the amount of mitochondrial protein.

Yilw is involved in the methylmercury-mediated transport of pyruvate into mitochondria in yeast. Significant differences were observed compared to the control group without methylmercury treatment.

Pyruvate is not converted to acetyl-CoA in the mitochondria matrix and is involved in methylmercury toxicity. Methylmercury causes mitochondrial dysfunction by promoting the uptake of pyruvate into the mitochondria in IMR cells. Cell viability was measured using an Alamar blue solution. Significant differences were observed compared to the control group without pyruvate treatment. Significant differences were observed relative to the control group without pyruvate treatment.