Mitochondria evolved from ancestral prokaryotes that were engulfed by primitive eukaryotes about 1.5 billion years ago. Their origin explains why mitochondria contain their own DNA (circularized, about 1% of the total cellular DNA), encoding roughly 1% of the total cellular proteins and approximately 20% of the proteins involved in oxidative phosphorylation. Although their genomes are small, mitochondria can nevertheless carry out all the steps of DNA replication, transcription, and translation. Interestingly, the mitochondrial machinery is similar to present-day bacteria; for example, mitochondria initiate protein synthesis with N-formylmethionine and are sensitive to antibacterial antibiotics. Moreover, since the ovum contributes the vast majority of cytoplasmic organelles to the fertilized zygote, mitochondrial DNA is virtually entirely maternally inherited. Nevertheless, because the protein constituents of mitochondria derive from both nuclear and mitochondrial genetic transcription, mitochondrial disorders may be X-linked, autosomal, or maternally inherited.

Mitochondria provide the enzymatic machinery for oxidative phosphorylation (and thus the relatively efficient generation of energy from glucose and fatty acid substrates). They also have an important role in anabolic metabolism and play a fundamental role in regulating programmed cell death, so-called apoptosis (Fig. 1).

Fig1. Roles of the mitochondria. Besides the efficient generation of ATP from carbohydrate and fatty acid substrates, mitochondria have an important role in intermediary metabolism, serving as the source of molecules used to synthesize lipids and proteins, and are also are centrally involved in cell life-and death decisions.

Energy Generation. Each mitochondrion has two separate and specialized membranes. The inner membrane contains the enzymes of the respiratory chain folded into cristae. This encloses a core matrix space that harbors the bulk of certain metabolic enzymes, such as the enzymes of the citric acid cycle. Outside the inner membrane is the intermembrane space, site of ATP synthesis, which is, in turn, enclosed by the outer membrane; the latter is studded with porin proteins that form aqueous channels permeable to small (<5000 daltons) molecules. Larger molecules (and even some smaller polar species) require specific transporters.

The major source of the energy to run all the basic cellular functions derives from oxidative metabolism. Mitochondria oxidize substrates to CO2, transferring the high-energy electrons from the original molecule (e.g., sugar) to molecular oxygen, and generating the low-energy electrons of water. The oxidation of various metabolites drives hydrogen ion (proton) pumps that transfer H+ from the core matrix into the intermembrane space. As the H+ ions flow back down their electrochemical gradient, the energy released is used in the synthesis of adenosine triphosphate (ATP).

It should be noted that the electron transport chain need not necessarily be coupled to ATP generation. Through the function of thermogenin, an inner membrane protein, the energy can be used to generate heat. Hence tissues with high levels of thermogenin, such as brown fat, can generate heat by non-shivering thermogenesis. As a natural (albeit usually low-level) byproduct of substrate oxidation and electron transport, mitochondria are also an important source of reactive oxygen species (e.g., oxygen free radicals, hydrogen peroxide); importantly, hypoxia, toxic injury, or even mitochondrial aging can lead to significantly increased levels of intracellular oxidative stress. Mitochondria are constantly turning over, with estimated half-lives ranging from 1 to 10 days, depending on the tissue, nutritional status, metabolic demands, and intercurrent injury.

Intermediate metabolism. As described in Chapter 7, pure oxidative phosphorylation produces abundant ATP, but also “burns” glucose to CO2 and H2O, leaving no carbon moieties suitable for use as building blocks for lipids or proteins. For this reason, rapidly growing cells (both benign and malignant) upregulate glucose and glutamine uptake and decrease their production of ATP per glucose molecule, a phenomenon called the Warburg effect. Both glucose and glutamine provide carbon moieties that prime the mitochondrial TCA cycle, but instead of being used to make ATP, intermediates are “spun-off” to make lipids, nucleic acids, and proteins . Thus, depending on the growth state of the cell, mitochondrial metabolism can be modulated to support either cellular maintenance or cellular growth. Ultimately, these metabolic decisions are governed by growth factors, nutrient and oxygen supplies, and cellular signaling pathways and sensors that respond to these exogenous factors.

Cell Death. In addition to providing ATP and metabolites that enable the bulk of cellular activity, mitochondria also regulate the balance of cell survival and death. There are two major pathways of cell death:

• Necrosis: External cellular injury (toxin, ischemia, trauma) can damage mitochondria, inducing the formation of mitochondrial permeability transition pores in the outer membrane. These channels allow the dissipation of the proton potential so that mitochondrial ATP generation fails and the cell dies.

• Apoptosis: Programmed cell death is a central feature of normal tissue development and turnover and can be triggered by extrinsic signals (including cytotoxic T cells and inflammatory cytokines), or intrinsic pathways (including DNA damage and intracellular stress). Mitochondria play a central role in the intrinsic pathway of apoptosis. If mitochondria are damaged (a sign of irreversible cell injury or stress) or the cell cannot synthesize adequate amounts of survival proteins (because of deficient growth signals), mitochondria become leaky. Cytochrome c, which is normally sequestered inside the mitochondria, leaks into the cytosol, where it forms a complex with other proteins that ultimately activate caspases, the enzymes that induce apoptosis. This process is described in more detail in Chapter 2. Failure of apoptosis can contribute to malignancy (Chapter 7) and too much apoptosis can lead to premature cell death, as occurs in some neurodegenerative disorders (Chapter 28).

Although mitochondria were discovered well over 100 years ago, the secrets of their functions continue to be unraveled.

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مواضيع ذات صلة

Stem Cells

Proliferation and the Cell Cycle

Growth Factors and Receptors

Signal Transduction Pathways

Cell Signaling

Waste Disposal: Lysosomes and Proteasomes

Biosynthetic Machinery: Endoplasmic Reticulum and Golgi

Cytoskeleton and Cell-Cell Interactions

Plasma Membrane: Protection and Nutrient Acquisition

Cytoplasmic Structures in Prokaryotic Cell

Eukaryotic Cell Structure

Cell Differentiation