Nanomedicine, Volume I: Basic Capabilities
© 1999 Robert A. Freitas Jr. All Rights Reserved.
Robert A. Freitas Jr., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX, 1999
Mitochondria are the principal chemical energy transducers of the eukaryotic cell under aerobic conditions.3384 Except for the 10 reactions of the glycolytic pathway, all of the ATP-generating capacity of eukaryotes lies within the mitochondria. Mitochondria are scattered throughout the cytoplasm in virtually all aerobic cells, with numbers ranging from ~300/cell for relatively inactive cells like lymphocytes up to 2000-3000/cell for very active cells such as liver, kidney tubule and cardiac muscle cells (where mitochondria may occupy up to 20% of total cell volume).531 Mitochondria are often clustered within the cell in regions of intense metabolic (hence ATP) demand. For instance, in muscle cells the mitochondria are organized in rows between adjacent contractive myofibrils in order to minimize the required diffusion distance for ATP molecules that are powering the activity. Similar localization appears in sperm tail flagella, in cilia, and at the base of kidney tubule cells where exchange with the blood is most rapid. Except for plant chloroplasts, mitochondria are unique among organelles in having their own DNA genomes, ribosomes and tRNAs that are quite different from those found in the cytoplasm.
After the nucleus, the mitochondrion is the largest organelle in most animal cells. The typical time-averaged dimensions are roughly cylindrical, with a 0.5-1.0 micron diameter and a ~3 micron length (and rarely, up to 10 microns)939 -- about the size of a bacterium or modest-sized medical nanodevice. Mitochondria are usually depicted as tiny kidney-bean or sausage-shaped organelles, but in living cells they squirm, flex, elongate, and change shape almost continuously (Fig. 8.40) in part due to cytoskeletal interactions. Mitochondria may be shuttled around a cell at up to ~10 microns/sec via dynein motors453 riding on microtubules (Section 18.104.22.168), bulging the plasma membrane as they travel.1249
Mitochondria have four functional compartments: outer membrane, intermembrane space, inner membrane, and the matrix. The outer surface is a smooth, featureless, 5-6 nm thick membrane938 embedded with many copies of a transport protein that forms large aqueous channels through the lipid bilayer, so the membrane is permeable to all molecules of mass <10,000 daltons (which includes all metabolites pertinent to mitochondrial function). Since mitochondria do not grow by fusion with vesicles synthesized elsewhere in the cell, transfer of phospholipids from the endoplasmic reticulum to the mitochondrion requires special phospholipid transfer proteins in the outer membrane (e.g., glycerolphosphate acyltransferase and monoacyl glycerolphosphate acyltransferase) that can recognize a specific kind of phospholipid, remove it from a vesicle membrane and add it to the mitochondrial membrane. Special enzymes such as monoamine oxidase, acyl-CoA synthetase, and phospholipase A2 are also present.996 The first 32 N-terminal amino acids of cytochrome c1 constitute a fixed "leader sequence" that is recognized as a matrix targeting signal and allows the tagged molecule admission through the outer membrane.997 Thus, as with other organelles, the outer coat of the mitochondrion should be immediately and uniquely recognizable by in cyto nanorobots equipped with suitable chemosensors (Section 4.2).
The intermembrane space also contains numerous unique proteins, as for example the essential multispanning carrier (chaperone) proteins Tim10p and Tim12p.1142
The 5-6 nm thick inner membrane is highly convoluted, forming a series of ~30 infoldings (each fold ~100 nm wide) known as cristae, which extend into the inner compartment or matrix, roughly quintupling the active surface area of the outer membrane (Fig. 8.41). The inner membrane is rich in cardiolipin, a phospholipid that accounts for 10% of the membrane lipid content and renders it unusually impermeable to most solutes. The inner membrane also contains a variety of special transport proteins that make it selectively permeable to those particular small molecules that are metabolized by mitochondrial enzymes concentrated in the matrix space,531 such as the integral membrane proteins Tim17, Tim 23, and Tim22p.1142 All of these membrane-specific proteins are readily detectable by nanorobots that are extending manipulators tipped with appropriately configured chemical sensors through the intermembrane space (Section 9.4.5).
The inner membrane is the locale of electron transport and ATP synthesis. A single mitochondrion has ~10,000 large protein F1 (ATP synthase) complexes embedded in its inner membrane, randomly distributed and typically measuring ~10-20 nm in diameter.939 These integral proteins freely diffuse laterally within the inner membrane. Mobility is high -- protein complexes collected at one end of a membrane by externally imposed electrophoretic forces return to a random distribution in just a few seconds.939
The prominence of cristae is correlated with the relative metabolic activity of the cell or tissue. Heart, kidney, and muscle cells have high respiratory activity levels, and their mitochondria have correspondingly large numbers of prominent cristae.531 The number of cristae is three times greater in the mitochondria of cardiac muscle cells than in hepatic mitochondria, reflecting the greater demand for ATP in heart tissue. The cristae of mitochondria in different cell types are not only different in number and deepness, but also in basic morphology (Fig. 8.42).531,3385-3388
The interior of the mitochondrion is filled with a semifluid gel-like matrix that contains a concentrated mixture of hundreds of different enzymes related to aerobic cellular respiration and oxidation, plus several identical copies of the mitochondrial DNA genome, special mitochondrial ribosomes, tRNAs, and various enzymes required to express the mitochondrial genes. The mitochondrial genome3073 consists of a circular DNA molecule of ~11 million daltons, coding for about a dozen polypeptides. It has 16,569 base pairs and a contour length of ~5 microns. Mitochondria are self-replicating organelles (with the help of cell-supplied proteins and lipids). When cellular requirements for ATP increase, mitochondria pinch in half (a process called fission) to increase their number, then both halves regrow to the former full size.940
Mitochondria also are sometimes found as extended reticular networks3177-3179 which are extremely dynamic in growing cells (such as mammalian fibroblasts), with tubular sections dividing in half, branching, and fusing to create a fluid tubular web.3179,3180
Last updated on 20 February 2003