Mitochondrial metabolism pathways

PFOA is thought to induce peroxisome proliferation and interfere with mitochondrial metabolic pathways. Direct measurements revealed that PFOA uncouple mitochondrial respiration by increasing... 

Figure 32.2 Effect of thiamine deficiency on mitochondrial energy metabolism illustrated with a scatter plot of relative expression from mitochondrial energy metabolism gene array. Array analysis shows Group 1 (thiamine deficiency) versus control (pair-fed control) expression in which numerous genes are downregulated (gray circles). In general, thiamine deficiency decreased the expression of many genes of the mitochondrial metabolic pathway.

R. Steuer, A. Nunes Nesi, A. R. Femie, T. Gross, B. Blasius, and J. Selbig, From structure to dynamics of metabolic pathways Application to the plant mitochondrial TCA cycle. Bioinfor matics 23(11), 1378 1385 (2007). 

The central dogma of apoptosis is that all the initiating pro-apoptotic stimuli converge on the mitochondrial compartment. Thus, although apoptosis can be initiated elsewhere, the execution phase of apoptosis induced by ionizing radiation needs mitochondria. How do DNA lesions trigger mitochondria Several metabolic pathways coimect mitochondria to the nucleus. 

The tricarboxylic acid cycle (TCA cycle, also known as the citric acid cycle or Krebs cycle) is a cyclic metabolic pathway in the mitochondrial matrix (see p. 210). in eight steps, it oxidizes acetyl residues (CH3-CO-) to carbon dioxide (CO2). The reducing equivalents obtained in this process are transferred to NAD"" or ubiquinone, and from there to the respiratory chain (see p. 140). Additional metabolic functions of the cycle are discussed on p. 138. 

The most important process in the degradation of fatty acids is p-oxidation—a metabolic pathway in the mitochondrial matrix (see p. 164). initially, the fatty acids in the cytoplasm are activated by binding to coenzyme A into acyl CoA [3]. Then, with the help of a transport system (the carnitine shuttle [4] see p. 164), the activated fatty acids enter the mitochondrial matrix, where they are broken down into acetyl CoA. The resulting acetyl residues can be oxidized to CO2 in the tricarboxylic acid cycle, producing reduced... 

The degradation of the fatty acids occurs in the mitochondrial matrix through an oxidative cycle in which C2 units are successively cleaved off as acetyl CoA activated acetic acid). Before the release of the acetyl groups, each CH2 group at C-3 of the acyl residue (the P-C atom) is oxidized to the keto group— hence the term p-oxidation for this metabolic pathway. Both spatially and functionally, it is closely linked to the tricarboxylic acid cycle (see p. 136) and to the respiratory chain (see p. 140). 

The function of the target molecule may be critical or mncritical. Thus, if the target molecule is an enzyme, this could be involved in a crucial metabolic pathway, such as mitochondrial oxidative phosphorylation. In this case, an adverse interaction with the ultimate toxicant is likely to lead to cell dysfunction and possibly death (e.g., as with cyanide or salicylate). Chemicals such as methimazole and resorcinol, which are activated to free radical intermediates by thyroperoxidase, cause destruction of the enzyme. This then disturbs thyroid hormone synthesis and thyroid function with pathological consequences such as thyroid tumors. 

As we noted in Chapter 16, the enzymes of many metabolic pathways are clustered (p. 605), with the product of one enzyme reaction being channeled directly to the next enzyme in the pathway. In the urea cycle, the mitochondrial and cytosolic enzymes appear to be clustered in this way. The citrulline transported out of the mitochondrion is not diluted into the general pool of metabolites in the cytosol but is passed directly to the active site of argininosuccinate synthetase. This channeling between enzymes continues for argininosuccinate, arginine, and ornithine. Only urea is released into the general cytosolic pool of metabolites. 

Fig. 10.5. Evolution of mitochondria and anaerobic organelles. Two possible scenarios for the evolution of diverse mitochondrial-derived organelles, (a) The aerobic and anaerobic metabolic pathways were present in the mitochondrial ancestor, followed by differential loss of functions in different extant eukaryote lineages, (b) The mitochondrial ancestor contained enzymes for aerobic metabolism, and the origin of anaerobes occurred via the acquisition of enzymes of anaerobic metabolism by lateral gene transfer (LGT). The order of gains and losses is unknown and the order depicted in the diagram is arbitrary...

Figure 12-2. Metabolic pathways involving the four biotin-dependent carboxylases. The solid rectangular blocks indicate the locations of the enzymes ACC, acetyl-CoA carboxylase PMCC, P-methylcrotonyl-CoA carboxylase PC, pyruvate carboxylase PCC, propionyl-CoA carboxylase. Isolated deficiencies of the first three carboxylases (mitochondrial) have been established (isolated ACC deficiency has not been confirmed). At least the activities of the three mitochondrial carboxylases can be secondarily deficient in the untreated multiple carboxylase deficiencies, biotin holocarboxylase synthetase deficiency and biotinidase deficiency. Lowercase characters indicate metabolites that are frequently found at elevated concentrations in urine of children with both multiple carboxylase deficiencies. The isolated deficiencies have elevations of those metabolites directly related to their respective enzyme deficiency.

HMG-CoA lyase is normally present in the mitochondrial matrix.To understand the complexity of the metabolic problems of a patient with HMG-CoA lyase deficiency, it is necessary to consider the role of this enzyme in two very distinct metabolic pathways catabolism of leucine and ketogenesis. 

Metabolic pathways such as the electron transport chain of mitochondrial respiration and biochemical reduction of oxygen by enzymes of xenobiotic metabolism,... 

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