Mitochondrial metabolite transport

Mitochondrial metabolite transporters (Data is taken from Refs. 6, 12 and 19)... 

In general, mechanistic studies of the mitochondrial metabolite transporters carried out in the last five years have provided evidence supporting a gated-pore, sequential model for transport. Structural studies of the adenine nucleotide carrier are more advanced than studies of the other transporters, and these provide the most clear cut evidence. 

Since many metabolic processes in the cell require the participation of both intra-and extramitochondrial enzyme reactions, transport of certain metabolites across the mitochondrial membrane is obligatory. Developments in the field of mitochondrial metabolite transport have been rapid in the last 15-20 years. Whereas most of this work during the first decade was carried out with isolated mitochondria (see [13] for review), during the last decade research gradually moved in the direction of elucidation of the role that these transport systems (translocators, carriers) play in the regulation of metabolism in the intact cell [4-7]. 

Since the reviews mentioned above have described the history of mitochondrial metabolite transport in great detail and since space is limited, in the present review we will highlight recent developments with emphasis on the possible regulatory role that the translocators play in integrating mitochondrial and cytosolic processes. 

Inhibition of mitochondrial metabolite transport by cxtramitochondrial metabolites... 

F. Wu, F. Yang, KC Vinnakota, and DA Beard, Computer modeling of mitochondrial tricarboxylic acid cycle, oxidative phosphorylation, metabolite transport, and electrophysio logy. J. Biol. Chem. 282(34), 24525 24537 (2007). 

Figure 7.44 The metabolism and toxicity of MPTP. Diffusion into the brain is followed by metabolism in the astrocyte. The metabolite MPP+ is actively transported into the dopaminergic neuron by DAT. It is accumulated there and is actively taken into mitochondria by another uptake system. Here, it inhibits mitochondrial electron transport between NADH dehydrogenase (NADH DHase) and coenzyme Q (Q10). Consequently, it blocks the electron transport system, depletes ATP, and destroys the neuron. Abbreviations MPTP, 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine DAT, dopamine transporter uptake system.

MPTP is a molecule, which is sufficiently lipophilic to cross the blood-brain barrier and enter the astrocyte cells. Once in these cells, it can be metabolized by monoamine oxidase B to MPDP and then MPP both of which are charged molecules. These metabolites are therefore not able to diffuse out of the astrocyte into the bloodstream and away from the brain. However, the structure of MPP allows it to be taken up by a carrier system and concentrated in dopaminergic neurones. In the neurone, it inhibits the mitochondrial electron transport chain leading to damage to the neurone. 

Figure 5.6. A diagrammatic summary of adjusted hypoxia response systems (the AHRS) proposed as the ancestral physiological phenotype and as a phylogenetic adaptation to hypobaric hypoxia. Summary based largely upon studies of Quechuas and Sherpas. Essentially all of the characteristics summarized here are also expressed in individuals well adapted for endurance performance. In the latter, the main modification involves an upwards regulation of mitochondrial volume densities at the working tissues (altered expression of mitochondrial metabolic enzymes and metabolite transporters above), which is why this is referred to as a high-capacity version of the lower capacity high-altitude phenotype. See text for further details. (Modified from Hochachka et al., 1999.)...

Piericidins are the first compounds obtained by the screening search for insecticidal natural products among microbial metabolites.10 They were isolated from Streptomyces mobaraensis in 1963,11 and many piericidin derivatives have been found in microbial metabolites until now.12 Piericidins are not used as insecticides practically, but are important biological reagents because they have specific inhibitory activity toward the mitochondrial electron transport chain protein nicotinamide adenine dinucleotide (NADH)-ubiquinone reductase (complex I).13 Piericidin Ax (1 in Figure 1) is biosynthesized as a polyketide,14 but genes responsible for its biosynthesis are not yet identified. Total synthesis of piericidins A (1) was reported recently.15... 

The level of another metabolite, formate, was also elevated in ALS and Hirayama patients. This metabolite is responsible for dismption of mitochondrial electron transport and energy production by inhibiting cytochrome oxidase activity. Cell death as a result of formate inhibition of cytochrome oxidase is believed to be the result of partial loss of ATP and, therefore, the loss of energy needed for basic cell functions. In addition, inhibition of cytochrome oxidase by formate can facilitate the production of cytotoxic reactive oxygen species, which also implies cell death. 

In some mammalian cells, enzymes comprising partial spans of biosynthetic pathways are inside and some outside the mitochondrial matrix space. Therefore, in the liver, six mitochondrial membrane transport proteins are required for urea synthesis, three for gluconeogenesis [7,8], and three others participate in ammonia-genesis [9] in the kidney. The synthesis of neurotransmitter substances such as acetylcholine, glutamate and y-amino butyric acid requires the participation of metabolite transporters in mitochondrial membranes of nervous tissue [9,10]. 

To date, twelve transporters with different substrate specificities have been demonstrated in mammalian mitochondrial membranes - (cf.. Table 8.1). Plant mitochondria have a slightly different set [11]. Early studies of metabolite transport in mitochondria dating from the middle 1960s were concerned with identifying these transporters. More recently, research has been directed toward elucidation of molec-... 

The availability of metabolites for sucrose synthesis and the need for products of sucrose degradation regulate gene expression. For respiration, sucrose is hydrolyzed by invertase to free glucose and fructose, which are phosphorylated and undergo glycolysis to pyruvate. The pyruvate is then either metabolized by mitochondrial electron transport to ATP and NADH (respiration), or metabolized to provide starting products for amino acid, lipid, and nucleotide syntheses. 

Atovaquone is an antimalarial preparation. It inhibits mitochondrial electron transport in parasites, causing inhibition of nucleic acid synthesis. Proguanil exerts its effect by means of the metabolite cycloguanil, which inhibits dihydrofolate reductase in the malarial parasite, disrupting deox-ythymidylate synthesis. It is indicated in prophylaxis of P. falciparum in patients with severe renal impairment (Ccr less than 30 mL/min) hypersensitivity to any component of the product. 

Cellular metabolites derived from mevalonic acid are required for cell proliferation. Cholesterol Is an essential component of cell membranes, farnesyl pyrophosphate is required to covalently bind to intracellular proteins and modify their function, ubiquinone is required for mitochondrial electron transport, and dolichol phosphates are required for glycoprotein synthesis. 

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